Insights into mechanisms behind arteriogenesis: what ... - CiteSeerX

Uncorrected Version. Published on August 4, 2008 as DOI:10.1189/jlb.0508281

Insights into mechanisms behind arteriogenesis: what does the future hold? Melany C. van Oostrom,*,1 Olivia van Oostrom,†,1 Paul H. A. Quax,‡,§ Marianne C. Verhaar,† and Imo E. Hoefer*,2 *Experimental Cardiology and †Vascular Medicine, University Medical Center Utrecht, the Netherlands; ‡ Biosciences, TNO Quality of Life, Leiden, the Netherlands; and §Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands

Abstract: Arteriogene sis, the enlargement of collateral vessels, seems a promising new target to improve blood flow to ischemic regions in patients suffering from cardiovascular conditions. With the growing knowledge of the mechanisms involved in arteriogenesis and the factors that influence the process, an increasing number of clinical trials are being performed to stimulate arteriogenesis, providing more insight in therapeutic opportunities for arteriogenesis. The expression of growth factors and the cooperation of surrounding and infiltrating cells seem to be essential in orchestrating the complex processes during arteriogenesis. In this review, we will discuss the regulating mechanisms of arteriogenesis, including the role of growth factors and different cell types and their implementation in a clinical setting. Furthermore, individual differences in the arteriogenic response will be considered, in light of the effect this will have on the success of therapeutic strategies to improve blood flow to ischemic tissue. J. Leukoc. Biol. 84: 000 – 000; 2008. Key Words: growth factors 䡠 cell therapy

INTRODUCTION Increased longevity and sedentary lifestyle are causing a significant increase in the morbidity of diseases such as type II diabetes, obesity, and hypertension. These “diseases of civilization”, attributed to the way of living in developed and developing countries, accelerate the development of atherosclerosis and often lead to cardiovascular complications. In fact, cardiovascular disorders are currently the leading cause of death globally [1]. Although successful therapies exist to reduce plaque formation and restore blood flow in patients suffering from ischemic vascular diseases, there is still a significant portion of patients who do not benefit from these treatment options. For a long time, it has been known that patients suffering from coronary heart disease can recruit collateral vessels and thereby improve symptoms of myocardial ischemia [2]. Also, it is well established that an increased demand in oxygen, as

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occurs during exercise and placental development, can induce formation of new capillaries [3]. Thus, it seems that the body already possesses an “in-house” rescue system to increase blood flow in ischemic circumstances. Stimulation of this system, termed neovascularization, could be a promising new direction in treating cardiovascular diseases. Neovascularization in humans can be fulfilled by three distinct mechanisms: vasculogenesis, angiogenesis, or arteriogenesis (depicted in Fig. 1) [4]. Although the latter does not refer to de novo formation of vessels but rather to enlargement of pre-existing arterioles, most authors use the term neovascularization for all three entities. Vasculogenesis refers to the in situ formation of blood vessels from circulating EPC [5]. Initially, this was thought only to occur during embryonic development; EPC (known as angioblasts during development) and hematopoietic stem cells arise from a common precursor, the hemangioblast, in the yolk sac of the developing embryo. Subsequently, angioblasts migrate, lengthen, interconnect, and establish a primitive vascular network. Studies have shown that vasculogenesis can also occur in some way in adulthood [6, 7]. Angiogenesis describes the process of growth of new blood vessels from pre-existing vessels. This happens in the growing embryo but also in the adult. As this process leads predominantly to the development of small capillaries, angiogenesis is unable to fully restore the function of larger vessels as a result of its limited size [8]. Angiogenesis is stimulated by ischemia and hypoxia signaling. Arteriogenesis is characterized by the enlargement of arteriolar anastomoses to collateral vessels through growth and proliferation. These vessels can grow considerably, enough even to take over the role of a large artery when occluded. In contrast to angiogenesis, arteriogenesis is independent of oxygen levels and usually occurs in a normoxic environment. It is instead promoted by changes in shear stress forces sensed by the vascular endothelium [9].

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These authors contributed equally. Correspondence: Laboratory of Experimental Cardiology, University Medical Center Utrecht, 3584 CX Utrecht, Heidelberglaan 100, the Netherlands. E-mail: [email protected] Received May 6, 2008; revised July 8, 2008; accepted July 8, 2008. doi: 10.1189/jlb.0508281 2

Journal of Leukocyte Biology Volume 84, December 2008

Copyright 2008 by The Society for Leukocyte Biology.

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Fig. 1. Neovascularization can occur via vasculogenesis (A), angiogenesis (B), or arteriogenesis (C). (A) In vasculogenesis, circulating endothelial progenitor cells (EPC; purple) contribute to new blood vessel growth (capillaries) by secreting the necessary growth factors and chemokines for endothelial cells to migrate (upper) or by incorporating into the newly formed vessels (lower). (B) During angiogenesis, endothelial cells are activated by ischemia and grow in the direction of angiogenic signals. The endothelial cells fuse and develop a lumen, thereby forming a new, small capillary vessel. (C) In arteriogenesis, circulating leukocytes (green) are attracted to the activated endothelium. They assist in enlarging collateral anastomoses. Activated endothelial cells (blue), activated vascular smooth muscle cells (yellow), quiescent endothelial cells (gray), quiescent smooth muscle cells (brown).

In this review, we will further discuss the regulating mechanisms of arteriogenesis, including the role of growth factors and different cell types and their implementation in a clinical setting. Furthermore, individual differences in the arteriogenic response will be considered in light of the effect that this will have on the success of therapeutic strategies to improve blood flow to ischemic tissue.

ARTERIOGENESIS The term “arteriogenesis”—the development of large collateral arteries from pre-existing arteriolar anastomoses—was proposed in 1997 by W. Schaper, R. Chapuli-Munoz, and W. Risau [10] to discriminate between arteriogenesis and true angiogenesis. Normally, as a result of the high resistance of arteriolar anastomoses and the lack of a pressure gradient, there is only a minimal net flow in these pre-existing connections. However, a sudden arterial occlusion or a slow progressing stenosis in the main artery can cause an increased pressure gradient in the anastomoses, leading to increased blood flow inside. These small vessels respond by actively proliferating and remodeling, which results in an increased lumen size and enhanced perfusion to the ischemic tissue [11]. Hence, it seems that arteriogenesis is initiated differently and progresses differently to angiogenesis.

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In this respect, Deindl et al. [12] demonstrated that arteriogenesis, in contrast to angiogenesis, is induced independently of hypoxia. They measured the expression of hypoxia-inducible factor 1␣ and other hypoxia-induced genes in a known animal model of arteriogenesis (rabbit hindlimb model) [13] and observed that none of the genes was up-regulated during collateral growth. Instead, the initial trigger for arteriogenesis was suggested to be fluid shear stress (FSS), the stress exerted by the blood on the endothelium as it flows by. Overall consensus, however, has not been reached, as FSS is a relatively weak force compared with other forces present in the artery (circumferential and radial wall stresses). Furthermore, FSS is almost impossible to measure in small collaterals. Interestingly, Pipp et al. [14] demonstrated the importance of FSS in arteriogenesis by means of a porcine ischemic hindlimb model with extremely high levels of collateral flow and FSS. Normally, during the later phases of arteriogenesis, FSS decreases as the collateral diameter increases so that FSS normalizes. This drop in FSS acts as a signal to arrest proliferation and as a result, prevents further collateral growth before an optimal adaptation is reached. Pipp and colleagues [14] demonstrated that sustained, elevated FSS in their arteriovenous shunt model further, significantly increased the size of collaterals, thus establishing that FSS is a dominant morphogenic power in collateral growth.

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Collaterals increase their diameter up to 20 times during arteriogenesis, which is possible through the mitosis of the vascular cells [15]. Given that the collateral vessels grow in length as well as in width, the expanding vessel arranges itself in loops and turns to accommodate the extra length. This gives the vessels a typical corkscrew pattern [16] and causes energy loss. This, together with the premature arrest of arteriogenic growth, as a result of the drop in FSS in the growing collateral, is a reason that collateral arteries cannot completely compensate the conductance of the artery they have replaced. Initially, during arteriogenesis, several collateral vessels are recruited and proliferate. However, as it is hemodynamically more efficient for fewer, larger arteries to conduct the blood than a greater number of smaller arteries, the smaller vessels regress later on, and those with the higher shear forces continue growing [17].

CELLULAR CONTRIBUTION TO ARTERIOGENESIS Endothelial cells [18] sense changes in FSS, which are transduced into biochemical signals. The precise molecular mechanism, by which endothelial cells transduce these mechanical stimuli into an intracellular response, is still unknown. Integrins [19], tyrosine receptor kinases [20, 21], G protein-coupled receptors [22], and ion channels [23, 24] have been proposed to act as shear stress sensors on the endothelial cell membrane. The signaling transduction cascades that are initiated as a result of the FSS lead to the activation of endothelial cells; expression of adhesion molecules is up-regulated (ICAM-1 [25], vascular cell adhesion molecule-1 [26]), production of several chemokines is increased (TNF-␣ [27, 28], GM-CSF) [29], and NO is released [30]. This leads to the next imperative step during the growth of collaterals: activation, adhesion, and migration of monocytes to the endothelium [26, 31, 32]. After maturation to macrophages, these circulating cells produce and secrete additional growth factors and cytokines such as basic fibroblast growth factor (bFGF) and TNF-␣, which contribute to the inflammatory environment of the anastomoses [33]. At this point, the monocytes have taken over the role of protagonist in the arteriogenic process from the endothelial cells. The essential role of monocytes is supported by studies providing evidence that enhanced attraction of monocytes (via MCP-1 administration [13]) or prolonged monocyte survival (GM-CSF [34]) correlates directly with augmented collateral and peripheral conductance after femoral artery occlusion. Correspondingly, diminished monocyte count (op/op mice [35]) or decreased monocyte adhesion (ICAM-1⫺/⫺ mice [25]) correlates with a reduced arteriogenic response. Besides monocytes, other circulating cells are also known to participate in the arteriogenic response. Lymphocytes are observed frequently in the wall of growing collaterals and thus, may also have a role in arteriogenesis [9] as they produce, e.g., vascular endothelial cell growth factor (VEGF) [36]. Their

specific role in arteriogenesis is uncertain. Activated T lymphocytes secrete cytokines and modulate trafficking of other inflammatory cells, such as monocytes/macrophages, and by doing so, may be able to participate in arteriogenesis. Mice deficient in CD4⫹ T lymphocytes showed reduced blood flow recovery after femoral artery ligation with concomitant, decreased recruitment of macrophages during arteriogenesis [37]. van Weel and colleagues [38] demonstrated in mice deficient in certain subsets of T cells that CD4⫹ T lymphocytes and NK cells are important for collateral vessel growth. The authors suggested that lymphocytes support arteriogenesis by contributing to the recruitment of monocytes to collateral vessels. Their specific role, their interaction with other cells such as monocytes/macrophages, and the sequence of events need to be unraveled yet. Usually, acute and chronic inflammatory processes can be distinguished by the predominant inflammatory cell type. Acute inflammation is characterized by invasion of neutrophils, accompanied and followed by monocytes/macrophages, whereas lymphocytes are usually considered a feature of chronic inflammation. Hence, a comparable series of events might also hold true for vessel growth. However, during angiogenesis and arteriogenesis, lymphocytes have been found at relatively early time-points [38], coinciding with the accumulation of monocytes/macrophages, which peaks after 2–3 days in a rabbit model of femoral artery occlusion [26]. Which cell type, if any, is the chicken or the egg or whether yetunknown molecules induce a concerted action of monocytes and lymphocytes (and possibly other subtypes) still remains to be elucidated in future studies. In any case, circulating cells may provide a powerful tool to modulate vessel growth, despite their involvement in atherogenesis. Macrophages are the main source for proteases such as matrix metalloproteinases [39]. These enzymes break down the surrounding tissue, i.e., the internal elastic lamina and the extracellular matrix (ECM), consequently allowing monocytes to invade the vascular wall further, enabling paracrine signaling between the endothelium and the perivascular cells [referred to as pericytes or smooth muscle cells (SMC)], and creating space for the growing vessel [40]. SMC slip away from each other as a result of the loss of ECM and intravascular pressure. This allows the vessel to enlarge, resembling a vein-like appearance [41]. Endothelium-derived platelet-derived growth factor B (PDGF-B) and PDGFR␤ expression on SMC play an important role in subsequent migration and recruitment of SMC to the subendothelial space, where they form the neointima layer [15, 42, 43]. The proliferating SMC arrange themselves around the growing vessel and exhibit a “synthetic” phenotype, entailing production of ECM, collagen, and elastin [15, 44]. In this manner, the SMC reconstitute the internal elastic lamina and the tunica media. Growth factors such as bFGF and TNF-␣ facilitate the proliferation phase of vascular cells, and they are secreted by monocytes or are already present in the tissue. The final phase in collateral growth is maturation of the vessels. This is characterized by reduced proliferation, migration and proteolytic activity, and the differentiation of SMC to the contractile phenotype [26].

van Oostrom et al. Future of arteriogenesis

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TABLE 1.

Overview of Clinical Trials in Patients with CAD

Trial

n

Therapeutic agent

Route of injection

Euroinject One [52]

40

VEGF-A165 plasmid

imc

KAT [53]

103

ic

AGENT [54] FIRST [55]

79 337

VEGF-A165 plasmid/ adenovirus FGF-4 adenovirus FGF-2 protein

VIVA [56]

178

VEGF-A165 protein

REVASC [57]

67

Zohlnho¨fer et al. [58] Seiler et al. [59] STEMMI [60] FIRSTLINE-AMI [61] REPAIR-AMI [62] Janssens et al. [63] BOOST [64] MAGIC CELL-3-DES [65]

114 21 78 50 58 67 60 96

Scha¨chinger et al. [66]

204

VEGF-A121 adenovirus G-CSF protein GM-CSF protein G-CSF protein G-CSF protein BMMNC BM stem cells BMMNC G-CSF-mobilized PBMNC BMMNC

Primary outcome

im

Improved regional wall motion; no improvement on myocardial perfusion after 3 months Increase in myocardial perfusion after 6 months in adenovirus group Favorable anti-ischemic effects at 4 weeks No improvement in exercise tolerance or myocardial perfusion at 180 days High dose resulted in improvement in angina class at 120 days Improvement in exercise-induced ischemia at 26 weeks

sc ic/sc sc sc ic ic ic ic

No improvement in infarct size reduction at 4–6 months Improvement in collateral growth in short-term protocol No further improvement in ventricular function after 6 months At 4 months, treatment is safe and signs of improvement Improvement after 4 months in coronary flow reserve No improvement in LVEF function after 4 months No improvement in LVEF after 18 months Improvement in LVEF after 6 months

ic ic ic/iv

ic

Improvement in LVEF after 4 months

imc, Intramyocardial; KAT, Kuopio Angiogenesis; ic, intracoronary; AGENT, Angiogenic Gene Therapy; FIRST, FGF Initiating Reva Scularization; VIVA, VEGF in Ischemia for Vascular Angiogenesis; REVASC, Recombinant Desulfatohirudin; im, intramuscular; STEMMI, Stem Cells in MI; FIRSTLINE-AMI, Front-Integrated Revascularization and Stem Cell Liberation in Evolving Acute MI; REPAIR-AMI, Reinfusion of Enriched Progenitor Cells in Infarct Remodeling in Acute MI; BMMNC, BM Mononuclear Cells; LVEF, left ventricular ejection fraction; BOOST, BM Transfer to Enhance ST-Elevation Infarct Regeneration; MAGIC CELL-3-DES, Myocardial Regeneration and Angiogenesis in MI with G-CSF and i.c. Stem Cell Infusion-3-Drug Eluting Stent; PBMNC, PBMC.

Bone marrow (BM)-derived circulating cells may also be involved in arteriogenesis. Adult BM is a rich reservoir of hematopoietic, mesenchymal stem, and progenitor cells. Asahara et al. [7] reported in 1997 the involvement of BM-derived cells in physiological and pathological vessel growth. Circulating CD34⫹ hematopoietic cells were able to incorporate into sites of active angiogenesis [7, 16, 45]. The recruitment of BM cells that are able to differentiate into SMC to perivascular sites in tumors is dependent on PDGF-PDGFR␤ signaling [46]. Inhibition of PDGFR␤ signaling eliminates PDGFR␤⫹ SMC in tumors leading to enlargement and hyperdilatation of tumor vessels, indicating that they play a role in regulation of vessel stability and vascular survival of tumors, although further studies are needed to elucidate their role in collateral artery growth. Irrespective hereof, it remains the subject of intense discussion whether circulating BM-derived cells incorporate into growing collateral arteries. Ziegelhoeffer and colleagues [47] showed that these cells do not incorporate into the vascular wall itself. The localization of BM-derived cells around the growing collateral arteries suggested a mere paracrine, supportive effect, indicating a role as cytokine and growth factor bullets [47]. Supporting this concept is a study demonstrating that marrow stromal cells can augment collateral remodeling through release of several cytokines rather than via incorporation into vessels [48]. Nevertheless, these studies indicate a stimulatory role, direct or indirect, of BM-derived cells in arteriogenesis, rendering BM cells an interesting target for clinical use.

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THERAPEUTIC STRATEGIES TO IMPROVE ARTERIOGENESIS A well-developed coronary collateral circulation is known to improve the survival rate after myocardial infarction (MI) and prevent the occurrence of cardiovascular events in coronary artery disease (CAD) patients [49]. However, many patients do not possess a sufficient collateral network [50]. It is well established that severe stenosis or vascular occlusion (95% luminal narrowing) is a potent stimulus of collateral growth [51], but studies have shown that numerous other factors, i.e., growth factors and several cell types, also influence collateral formation (clinical trials are presented in Tables 1 and 2).

Growth factors The VEGF family consists of several family members, including splicing variants, VEGFA, VEGFB, VEGFC, VEGFD, and placental growth factor (PlGF) with each presenting itself in several isoforms. VEGFC and VEGFD regulate lymphatic angiogenesis; however, the role of VEGFB in vivo is unclear. VEGFA, also known as VEGF, is the key regulator of blood vessel growth, mainly by stimulating the migration and proliferation of endothelial cells [76, 77]. VEGFA also acts as a survival factor for endothelial cells, induces vasodilation (through NO), and increases vascular permeability [77]. Additionally, VEGF is known to stimulate the recruitment of monocytes [78], which are also involved in angiogenesis [10]. VEGF binds to two distinct receptor tyrosine kinases: VEGFR1 (fms-


TABLE 2. Trial Nikol et al. [67] VEGF peripheral vascular disease [68] RAVE [69]

n 107 54

Overview of Clinical Trials in Patients with Peripheral Arterial Disease (PAD) Therapeutic agent FGF-1 plasmid

Route of injection

Primary outcome

im

Reduced risk of amputation; no effect on ulcer healing at 25 weeks Increase in vascularity after 3 months

local, catheter-mediated

105

VEGF-A165 plasmid/ adenovirus VEGF121 adenovirus

TRAFFIC [70] Kusumanto et al. [71]

190 54

FGF-2 protein VEGF-A165 plasmid

ia im

HGF-STAT [72]

104

HGF plasmid

im

START [73] Huang et al. [74]

40 28

sc im

TACT [75]

52

GM-CSF protein G-CSF-mobilized PBMNC BMMNC/PBMNC

im

im

No improvement in peak walking time at 26 weeks Improvement in peak walking time at 90 days Clinical and hemodynamic improvements; no improvement in amputation rate at 100 days Safe and increase in limb perfusion in highdose group at 6 months No improvement in walking time at 90 days Improvement in lower limb pain and ulcer healing at 3 months Improvement in ankle-brachial index and rest pain at 24 weeks

RAVE, Regional Angiogenesis with Vascular Endothelial Growth Factor; TRAFFIC, Therapeutic Angiogenesis with Recombinant FGF-2 for Intermittent Claudication; ia, intra-arterial; HGF-STAT, Hepatocyte Growth Factor Plasmid to Improve Limb Perfusion in Patients with Critical Limb Ischemia; START, Stimulation of Arteriogenesis; TACT, Trial to Assess Chelation Therapy.

like tyrosine kinase receptor 1) and VEGFR2 (kinase insert domain containing region/fetal liver kinase-1). It is suggested that VEGFR2 is the main receptor conveying the mitogenic, chemotactic, and survival effects of VEGF in endothelial cells [77, 79]. VEGFR1, on the other hand, is expressed exclusively by monocytes and probably mediates VEGF-induced monocyte recruitment [78]. VEGF and bFGF have been tested extensively in animal models to assess whether they can augment the arteriogenic response. VEGF has been found to enhance perfusion and rescue ischemic tissues in preclinical animal studies [80, 81]. In the subsequent VIVA clinical trial, improvements in exercise results and angina symptoms were observed in patients after 120 days of recombinant VEGF protein administration [56]. Delivery of VEGF plasmid DNA or protein to ischemic hindlimb models enhanced perfusion rates in an arteriogenic manner [82, 83]. Also, secretion of VEGF by implanted myoblasts in the ischemic hindlimb of the mouse was able to increase the number and diameter of collaterals [84]. i.m. delivery of VEGF plasmid DNA has been applied with different success rates in patients, initially, in the open label studies of Isner et al. [85] and later, in double-blind, placebo-controlled studies [71], recently reviewed in ref. [86]. However, expression of VEGF and its receptors is unchanged during spontaneous arteriogenesis, and inhibition of VEGF signaling during arteriogenesis has no effect [11, 12]. It was demonstrated in a mouse hindlimb ischemia model that VEGF overexpression did not induce new collaterals but had a profound effect on capillary formation [87]. It is therefore thought that VEGF contributes to arteriogenesis indirectly through monocyte activation and stimulation of monocyte migration [88]. Caution should be noted with VEGF administration, as it can lead to hypotension and edema [89, 90]. Whether this is a result of enhanced vascular permeability or the formation of immature vessels by VEGF is uncertain.

Combinational therapy with a vessel-maturing agent might be a solution in the latter case. PlGF is a distinctive member of the VEGF family. Unlike the leaky capillaries induced by VEGF, PlGF can stimulate the growth of larger collateral vessels/arteriogenesis [91]. Moreover, PlGF-deficient mice show reduced collateral formation [92]. PlGF is a specific ligand for VEGFR-1, the monocytespecific VEGFR, and when bound, activates and recruits monocytes to growing collateral vessels [91]. PlGF thus seems an attractive potentiator of arteriogenesis, particularly, as it does not cause side-effects associated with VEGF, such as hypotension and edema [93]. Interestingly, its effects are increased when administered simultaneously with VEGF-A [93]. The FGF family consists of more than 20 polypeptides that mediate a broad range of activities in several cell types. FGF-2 (also known as bFGF) plays an important role in growing collaterals; it is secreted by the recruited monocytes and induces the proliferation of SMC, which are needed for vessel maturation [94]. FGF-1 (also known as aFGF), on the other hand, can effectively stimulate monocyte adhesion, contributing to the inflammatory environment surrounding the growing collaterals. Administration of bFGF [95, 96] or aFGF [97, 98] (by recombinant protein or gene delivery) to different ischemic animal models has been shown to induce arteriogenesis and increase performance outputs. In the first clinical trial with FGF, Lederman et al. [70] described increased peak walking times at 90 days in patients with PAD receiving a single i.a. infusion of bFGF. In FIRST, a single i.c. bolus of bFGF also improved symptoms of patients with coronary heart disease at 90 days [55]. Unfortunately, these effects were not sustained at 180 days. In these trials too, dose-limiting side-effects were observed, such as hypotension and proliferative membranous nephropathy [99]. Another growth factor with promising results in animal studies of arteriogenesis is TGF-␤1. The role of TGF-␤1 in arte-


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riogenesis came to light when its levels were seen to be increased in the nonischemic myocardium during collateral growth [100]. This cytokine is known to attract circulating monocytes and activate SMC, both key processes involved in arteriogenesis [101, 102]. Correspondingly, exogenous administration of TGF-␤1 enhances collateral growth [102]. This growth factor is even more interesting, as it appears to favor the development of stable atherosclerotic lesions by suppressing T cell activation and stimulating fibrosis [103, 104]. Recently, a TGF-␤1-eluting stent, implanted in rabbits that subsequently underwent femoral artery ligation, proved to efficiently stimulate collateral artery growth [105]. The recruitment of monocytes is an important step during collateral growth. MCP-1, a chemokine expressed by endothelial cells, is actively involved in this process [106]. It is expressed in response to shear stress and exerts a chemoattractant effect on monocytes [107]. Mice deficient in MCP-1 show reduced blood flow after femoral artery ligation, compared with wild-type [108]. Accordingly, local infusion of MCP-1 accelerates arteriogenesis upon femoral artery ligation in rabbits [13]. Treatment with antibodies against ICAM-1, an adhesion molecule involved in monocyte adhesion to the endothelium, abrogated this stimulatory effect of MCP-1, suggesting that the MCP-1 exerts its effects through recruitment of monocytes [25]. However, studies in CCR2⫺/⫺ mice show discrepancies in the involvement of CCR2, the receptor for MCP-1, in collateral artery growth [31, 109]. Heil et al. [ ] reported that CCR2 signaling is essential in sites of active arteriogenesis in a mouse model for femoral artery ligation. Interestingly, others have shown that CCR2 is not of importance in physiological arteriogenesis in a femoral artery excision model. Differences in animal injury and strain differences between mice may explain the inconsistent results. Local accumulation of monocytes and macrophages is also a feature of atherosclerosis, and MCP-1 is highly expressed in atherosclerotic lesions [110]. As atherosclerotic disease is the major cause of insufficient tissue perfusion, aggravation of atherosclerosis is a concern with the possible therapeutic application of MCP-1 to stimulate arteriogenesis. van Royen et al. [111] found that local infusion of MCP-1 in apolipoprotein E-deficient mice, a hyperlipidemic mouse model, indeed leads to increased atherosclerotic plaque formation, neointimal formation, and monocyte activation and besides an increase in collateral flow, also resulted in a shift in cellular composition of the plaque toward a more unstable phenotype. These findings highlight the importance of testing potential therapeutic agents in “diseased” animal models [111, 112]. GM-CSF is produced by, e.g., endothelial cells [29]. It enhances the survival of monocytes by reducing apoptosis and has been shown to stimulate arteriogenesis in different tissues (hindlimb, brain, and heart) [113, 114]. Clinically, GM-CSF is particularly interesting, as it can lower plasma cholesterol levels by enhancing low-density lipoprotein clearance of the circulation and has been shown to reduce plaque surface in hyperlipidemic rabbits [115, 116]. Seiler et al. [59] demonstrated in a small, double-blind, placebo-controlled clinical study that local i.c. and s.c. injection of GM-CSF significantly improved coronary collateral blood flow after 14 days in CAD

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patients. However, a sequential study to test safety and efficacy of GM-CSF in CAD patients was ended prematurely, as two of the seven patients receiving GM-CSF suffered from an acute coronary syndrome with occlusion of a coronary artery [117]. Although collateral growth was enhanced, leukocyte accumulation in atherosclerotic lesions may have led to plaque rupture. In the START trial, s.c. administration of GM-CSF in patients with PAD was not sufficient to increase walking times, the primary end-point of the pilot study [73]. This was attributed to a suboptimal dosage, as blood levels of monocytes increased only temporarily after GM-CSF infusion, before finally dropping below baseline at Day 14. It was also suggested that stimulation of arteriogenesis might be more difficult in PAD patients, as a long period of time elapses between the onset of the disease and interventional therapy, in contrast to CAD patients in which symptoms are more severe and detected earlier. Alternatively, G-CSF can be used to improve tissue perfusion. This cytokine mobilizes BM-derived cells and has been demonstrated to reduce myocardial damage and mortality after MI in pigs [118]. Orlic et al. [119] has shown that treatment with G-CSF and stem cell factor, another mobilizer of BMderived cells, to the injured myocardium of mice resulted in myocardial regeneration, characterized by dividing myocytes and formation of vascular structures. Previously, G-CSF-mobilized human cells were demonstrated to stimulate vasculogenesis and angiogenesis in the infarcted myocardium of rats [120]. These results suggest that G-CSF mobilizes BM cells, which home to the damaged area and differentiate into cells of the appropriate tissue. However, the effect of G-CSF may be more subtle. G-CSFRs are expressed on circulating cells, cardiomyocytes, and endothelial cells [121], and G-CSF signaling is known to promote cell survival and Akt expression [118]. Correspondingly, Deindl et al. [121] demonstrated that G-CSF administration after MI enhanced arteriogenesis. The first clinical study, FIRSTLINE-AMI to use G-CSF treatment after acute MI observed improvement in cardiac function after the 1-year follow-up and no adverse effects [61]. However larger, double-blind studies reported no improvements in myocardial function after acute MI and possible severe, adverse outcomes [60, 122]. It is clear that growth factor therapy needs careful monitoring and extensive testing in different models in which preclinical animal models are of importance. Up until now, clinical trials have focused mainly on functional outcomes; therefore, it is unknown whether these studies ameliorated neovascularization effectively in the myocardium.

Cell therapy Cell-based approaches for neovascularization use BM-derived or peripheral blood-derived progenitor cells to stimulate this process in ischemic tissues. In the first randomized and controlled trial BOOST, i.c. injection of BM cells was performed in patients after acute MI and successful percutaneous coronary intervention. This treatment improved left ventricular function at 6 months but not after 18 months compared with the control group [64]. The placebo-controlled REPAIR-AMI study also


used i.c. injection of BM cells and reported after 4 months a positive influence of BM cells on left ventricular ejection fraction and additionally in coronary flow reserve [62, 66]. Furthermore, after 12 months, patients who had received BM cells experienced less clinical events, such as death or MI, than patients that had been administered the placebo [123]. Subgroup analysis suggested that the benefit was greatest in patients with the worst left ventricular ejection fraction at baseline. The MAGIC Cell-3-DES trial showed that i.c. infusion of peripheral blood stem cells (PBMNC), mobilized with G-CSF, also increased left ventricular function after 6 months in revascularized patients with a drug-eluting stent [65]. Although, there were initial concerns about in-stent restenosis induced by G-CSF, as observed in earlier trials, this was not detected in the MAGIC CELL-3 DES study. Meta-analysis studies of clinical trials, involving i.c. or i.m. injection of patients’ own blood or BM-derived cells to stimulate cardiac repair, have reported that the therapy is safe and that there are clinically relevant benefits on cardiac function and remodeling in patients with acute myocardial function and ischemic heart disease. Therefore, data support the onset of large, multicenter, randomized trials to evaluate the impact of cell therapy on overall, long-term survival in these patients and to compare this treatment with the already implemented, standard care on patient outcomes [124, 125]. Also, PAD patients may benefit from cell therapy. i.m. injection of BMMNC into the calf muscle of the ischemic leg of PAD patients significantly improved walking capacity and perfusion registered by angiography [75, 126]. Beneficial clinical effects have also been shown of i.a. or combined i.a. and i.m. injection of BM cells or PBMNC in PAD [127]. However, it has not been reported whether these effects sustained longer than 6 months. Together, these trials demonstrate that cell-based therapy can significantly improve ventricular function, probably by ameliorating perfusion; however, they are not conclusive. The benefit is moderate, and it is unclear in which way the cells contribute to the effects, by incorporation into new capillaries or by secretion of angiogenic and arteriogenic factors. In line with this query, animal studies have been performed using these cells as carriers of arteriogenic factors. The fact that monocytes orchestrate the arteriogenic process through sequential expression of cytokines and growth factors resulted in the concept of using monocytes as a vehicle to deliver proarteriogenic factors. Herold et al. [128] i.v.-injected autologous monocytes infected with GM-CSF constructs in rabbits with ligated femoral arteries and observed increased arteriogenesis in these animals. This effect was also observed when monocytes were injected 7 days after femoral ligation. Thus, monocytes prove to be an efficient delivery method for GM-CSF treatment and could even be used for combined treatment with other proarteriogenic factors such as TGF-␤1 or bFGF. This strategy is probably more potent than systemic administration, as higher cytokine concentrations can be reached locally without causing systemic side-effects. Translation to the clinical situation seems attractive, as monocyte isolation can be done easily in humans, and injection of in vitro grown cells has been performed already without adverse effects [129]. Nevertheless,

as with all proarteriogenic therapies, safety issues regarding stimulation of pathological angiogenesis (tumor angiogenesis, diabetic retinopathy, and intraplaque angiogenesis) need to be considered.

Ongoing trials in cell and growth factor therapy In the past, clinical trials have focused, in a large part, on growth factor therapy via gene transfer or injection of recombinant proteins. Despite a variety of attempts to modulate dosage, methods of administration, and vectors to enable longterm gene expression, results from these trials have been mixed. This has resulted in the investigation and development of additional methods to stimulate arteriogenesis. As summarized in Tables 3 and 4, current, ongoing trials are focusing predominantly on the application of BM cells. These trials will also reveal whether it is more beneficial to use certain purified subsets of BM cells as well as which delivery method to the target tissue is most optimal. Previous studies have taught us the importance of performing large, randomized, placebo-controlled trials rather than pilot trials to fully elucidate the benefit of the above-mentioned therapies in patients with CAD or PAD. Moreover, much more efforts are needed to identify the target patient population, as experimental clinical trials only include no-option patients. Given the strong placebo effect, long follow-up periods are warranted to reveal long-term benefits and potential sideeffects of growth factor or cell therapy.

INDIVIDUAL DIFFERENCES IN COLLATERAL GROWTH Studies have shown that with increasing age, the degree of collateralization decreases in patients after acute MI and with longstanding angina [49]. Moreover, diseases can negatively influence collateral formation; it has been shown that patients with diabetes are less able to form a well-developed collateral network [130]. This was suggested to be the consequence of endothelial dysfunction caused by hyperglycemia. Later, Waltenberger [131] demonstrated that monocyte function is reduced in diabetic patients; the chemotactic response of monocytes to VEGF was decreased. Hypercholesterolemia, another cardiovascular risk factor, also affects endothelial function and monocyte function; therefore, it was proposed that collateral growth is impaired in subjects with high cholesterol levels [132]. Accordingly, hypercholesterolemic mice have a delayed arteriogenic response as a result of reduced monocyte and macrophage accumulation [133]. Furthermore, van Weel et al. [112] have demonstrated in mice that arteriogenesis following femoral artery ligation is more reduced by hypercholesterolemia than by hyperglycemia. However, there are no clinical studies that support the negative influence of cholesterol on collateralization. In contrast, a positive relation has been reported between high cholesterol levels and collateral formation [134]. Genetic or molecular differences may also account for differences in the ability to form collaterals. Identification of these


7

TABLE 3.

NCT number

Overview of Ongoing Clinical Trials on Therapeutic Angiogenesis in Patients with CAD

Sponsor

Route of injection

Therapeutic agent

NCT00694642 NCT00384982

investigator investigator

CD133⫹BMC BMMNC

NCT00669227 NCT00690209


BMMNC BMMNC

NCT00350766 NCT00437710 NCT00418418 NCT00200707 NCT00587990 NCT00462774

BMMNC BMMNC BMMSC BMMNC BMMSC CD133⫹BMC

NCT00215124 NCT00316381 NCT00529932

investigator investigator investigator investigator investigator investigator/ industry investigator investigator investigator

Recombinant G-CSF BMMNC/CD34⫹CXCR4⫹BMC CD133⫹BMC

sc ic ic

NCT00355186

investigator

BMMNC

ic

Primary outcome

transendocardial ic/imc ic im ic ic transmyocardial ic imc imc

Major adverse events Changes in resting myocardial perfusion defect size; changes in global LVEF LVEF Evaluation of left-ventricular volumes and contractility LVEF Mortality, morbidity, left-ventricular function LVEF Change in myocardial viability Incidence of serious adverse events LVEF Death, myocardial rupture, change in LVEF LVEF Progression in coronary atherosclerosis burden; change in myocardial thickening in leftventricular wall LVEF

LNCT, National Clinical Trial.

factors, which render a person less or more susceptible to collateral formation, may help in discovering new treatments to enhance collateral growth. A genetic study showed that the haptoglobin phenotype correlates with the development of the coronary artery circulation in diabetic patients with CAD [135]. Furthermore, the Asp298 allele of the endothelial NO synthase gene is associated with impaired collateral development, especially in patients with diabetes mellitus [136]. As circulating monocytes have a key role during arteriogenesis, Chittenden et al. [137] hypothesized differences in monocyte function to be responsible for differences in collateral growth. By comparing transcriptional profiles of circulating monocytes from CAD patients between those with well-developed collaterals and those without, molecular determinants for TABLE 4.

collateral growth were identified [137]. Differences were observed in genes regulating intracellular transport, apoptosis, and cell proliferation. For example, ICAM-1 and Cdc42 expression was increased in CAD patients with extensive collateralization, compared with CAD patients without. Increased ICAM-1 levels probably reflect an enhanced inflammatory state of the monocytes, which is beneficial for collateral growth [25]. Cdc42, a small GTPase of the Rho family, has a role in monocyte/macrophage migration. Hence, its increased expression is also in line with augmented arteriogenesis. Interestingly, the transcriptional differences were independent of CAD severity. A recent study showed differential transcriptomes of stimulated monocytes from patients with single-vessel CAD and

Overview of Ongoing Clinical Trials on Therapeutic Angiogenesis in Patients with PAD

Sponsor

Therapeutic agent

Route of injection

NCT00371371 NCT00392509

investigator industry

BMMNC ALDHbr BMMNC

ia im

NCT00434616 NCT00311805


BMMNC CD34⫹BMC

im im

NCT00468000 NCT00539266

industry investigator

BMMNC BMMNC

im im

NCT00304837 NCT00566657

investigator industry

VEGF gene FGF-1 gene

im im

NCT00498069 NCT00616980

industry industry

BM concentrate CD34⫹BMC

im im

NCT number

Primary outcome Major amputation Adverse events, ankle-brachial systolic pressure index, transcutaneous oxygen value, quality of life Major amputation or unchanged critical limb ischemia Safety of im injection of CD34⫹ cells; functional improvement Time to treatment failure Limb salvage/wound-healing; pain-free walking distance Changes in rest pain and/or heals ulcers Time to major amputation of treated leg or death from any cause – Safety of im injection of CD34⫹ cells; changes in rest pain, ulcer healing, functional improvement, limb salvage

ALDHbr, Aldehyde dehydrogenase bright; –, unknown primary outcome.

8



differing arteriogenic collateral response after measuring the collateral flow index. The expression of IFN-␤ and IFN-related genes was increased in stimulated monocytes from patients with a poor arteriogenic response. Thus, IFN-␤ signaling may act as a novel target for stimulation of collateral artery growth. This supports the evidence of the impact of differences in signaling pathways in individual patients on arteriogenic response. This will be of major importance in formulating and investigating future therapeutic targets for stimulating collateral artery growth [138].

PERSPECTIVES It is becoming clear that besides cardiovascular risk factors, also, genetic factors heavily influence coronary collateral vessel growth. This is consistent with findings from clinical trials in which patients with a similar background responded differently to therapeutic neovascularization. Identification of markers of collateral growth could help in determining patient prognosis and predicting therapy response and maybe even lead to new, proarteriogenic therapies. Furthermore, concomitant administration of growth factors and cells may prove to be the most beneficial manner to orchestrate the whole arteriogenic process. However, hurdles still exist in this field, such as the optimal delivery method, dosage, and choice of growth factor or cell type. The diversity of approaches applied in clinical trials might hold the key to the observed discrepancy in results. Development of preclinical animal models (preferably large animal models such as pigs) is needed to test these methods, as extreme caution needs to be taken when extrapolating research in mice to the clinical setting. This will also enable further investigation of mechanisms, e.g., signaling molecules involved in collateral artery growth, extending our knowledge, and possibilities in therapeutic application. Future research will therefore involve investigation of the mechanisms behind the individual response to arteriogenesis and its relation to growth factor and cell therapy for the development of novel, therapeutic strategies.

ACKNOWLEDGMENT This work was supported by the Netherlands Organization for Scientific Research NWO (M. C. V. and I. E. H).

REFERENCES 1. World Health Organization (February 2007) Factsheet 317. 2. Helfant, R. H., Vokonas, P. S., Gorlin, R. (1971) Functional importance of the human coronary collateral circulation. N. Engl. J. Med. 284, 1277–1281. 3. Prior, B. M., Yang, H. T., Terjung, R. L. (2004) What makes vessels grow with exercise training? J. Appl. Physiol. 97, 1119 –1128. 4. Carmeliet, P. (2000) Mechanisms of angiogenesis and arteriogenesis. Nat. Med. 6, 389 –395.

5. Konkle, B. A., Schafer, A. I. (2005) Hemostasis, thrombosis, fibrinolysis, and cardiovascular disease. Braunwald’s Heart Disease 7th edition (D.P. Zipes et al., eds.), Philadelphia, PA, USA, Saunders. 6. Takahashi, T., Kalka, C., Masuda, H., Chen, D., Silver, M., Kearney, M., Magner, M., Isner, J. M., Asahara, T. (1999) Ischemia- and cytokineinduced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat. Med. 5, 434 – 438. 7. Asahara, T., Murohara, T., Sullivan, A., Silver, M., van der Zee, R., Li, T., Witzenbichler, B., Schatteman, G., Isner, J. M. (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275, 964 –967. 8. Scholz, D., Ziegelhoeffer, T., Helisch, A., Wagner, S., Friedrich, C., Podzuweit, T., Schaper, W. (2002) Contribution of arteriogenesis and angiogenesis to postocclusive hindlimb perfusion in mice. J. Mol. Cell. Cardiol. 34, 775–787. 9. Heil, M., Schaper, W. (2004) Influence of mechanical, cellular, and molecular factors on collateral artery growth (arteriogenesis). Circ. Res. 95, 449 – 458. 10. Ito, W. D., Arras, M., Scholz, D., Winkler, B., Htun, P., Schaper, W. (1997) Angiogenesis but not collateral growth is associated with ischemia after femoral artery occlusion. Am. J. Physiol. 273, H1255–H1265. 11. Schaper, W., Scholz, D. (2003) Factors regulating arteriogenesis. Arterioscler. Thromb. Vasc. Biol. 23, 1143–1151. 12. Deindl, E., Buschmann, I., Hoefer, I. E., Podzuweit, T., Boengler, K., Vogel, S., van Royen, N., Fernandez, B., Schaper, W. (2001) Role of ischemia and of hypoxia-inducible genes in arteriogenesis after femoral artery occlusion in the rabbit. Circ. Res. 89, 779 –786. 13. Ito, W. D., Arras, M., Winkler, B., Scholz, D., Schaper, J., Schaper, W. (1997) Monocyte chemotactic protein-1 increases collateral and peripheral conductance after femoral artery occlusion. Circ. Res. 80, 829 – 837. 14. Pipp, F., Boehm, S., Cai, W. J., Adili, F., Ziegler, B., Karanovic, G., Ritter, R., Balzer, J., Scheler, C., Schaper, W., Schmitz-Rixen, T. (2004) Elevated fluid shear stress enhances postocclusive collateral artery growth and gene expression in the pig hind limb. Arterioscler. Thromb. Vasc. Biol. 24, 1664 –1668. 15. Wolf, C., Cai, W. J., Vosschulte, R., Koltai, S., Mousavipour, D., Scholz, D., Afsah-Hedjri, A., Schaper, W., Schaper, J. (1998) Vascular remodeling and altered protein expression during growth of coronary collateral arteries. J. Mol. Cell. Cardiol. 30, 2291–2305. 16. Heil, M., Eitenmuller, I., Schmitz-Rixen, T., Schaper, W. (2006) Arteriogenesis versus angiogenesis: similarities and differences. J. Cell. Mol. Med. 10, 45–55. 17. Hoefer, I. E., Piek, J. J., Pasterkamp, G. (2006) Pharmaceutical interventions to influence arteriogenesis: new concepts to treat ischemic heart disease. Curr. Med. Chem. 13, 979 –987. 18. Davies, P. F. (1995) Flow-mediated endothelial mechanotransduction. Physiol. Rev. 75, 519 –560. 19. Jalali, S., del Pozo, M. A., Chen, K., Miao, H., Li, Y., Schwartz, M. A., Shyy, J. Y., Chien, S. (2001) Integrin-mediated mechanotransduction requires its dynamic interaction with specific extracellular matrix (ECM) ligands. Proc. Natl. Acad. Sci. USA 98, 1042–1046. 20. Chen, K. D., Li, Y. S., Kim, M., Li, S., Yuan, S., Chien, S., Shyy, J. Y. (1999) Mechanotransduction in response to shear stress. Roles of receptor tyrosine kinases, integrins, and Shc. J. Biol. Chem. 274, 18393– 18400. 21. Jin, Z. G., Ueba, H., Tanimoto, T., Lungu, A. O., Frame, M. D., Berk, B. C. (2003) Ligand-independent activation of vascular endothelial growth factor receptor 2 by fluid shear stress regulates activation of endothelial nitric oxide synthase. Circ. Res. 93, 354 –363. 22. Chachisvilis, M., Zhang, Y. L., Frangos, J. A. (2006) G protein-coupled receptors sense fluid shear stress in endothelial cells. Proc. Natl. Acad. Sci. USA 103, 15463–15468. 23. Davies, P. F., Barbee, K. A., Volin, M. V., Robotewskyj, A., Chen, J., Joseph, L., Griem, M. L., Wernick, M. N., Jacobs, E., Polacek, D. C., dePaola, N., Barakat, A. I. (1997) Spatial relationships in early signaling events of flow-mediated endothelial mechanotransduction. Annu. Rev. Physiol. 59, 527–549. 24. Nilius, B., Droogmans, G. (2001) Ion channels and their functional role in vascular endothelium. Physiol. Rev. 81, 1415–1459. 25. Hoefer, I. E., van Royen, N., Rectenwald, J. E., Deindl, E., Hua, J., Jost, M., Grundmann, S., Voskuil, M., Ozaki, C. K., Piek, J. J., Buschmann, I. R. (2004) Arteriogenesis proceeds via ICAM-1/Mac-1- mediated mechanisms. Circ. Res. 94, 1179 –1185. 26. Scholz, D., Ito, W., Fleming, I., Deindl, E., Sauer, A., Wiesnet, M., Busse, R., Schaper, J., Schaper, W. (2000) Ultrastructure and molecular histology of rabbit hind-limb collateral artery growth (arteriogenesis). Virchows Arch. 436, 257–270.


9

27. Hoefer, I. E., van Royen, N., Rectenwald, J. E., Bray, E. J., Abouhamze, Z., Moldawer, L. L., Voskuil, M., Piek, J. J., Buschmann, I. R., Ozaki, C. K. (2002) Direct evidence for tumor necrosis factor-␣ signaling in arteriogenesis. Circulation 105, 1639 –1641. 28. Luo, D., Luo, Y., He, Y., Zhang, H., Zhang, R., Li, X., Dobrucki, W. L., Sinusas, A. J., Sessa, W. C., Min, W. (2006) Differential functions of tumor necrosis factor receptor 1 and 2 signaling in ischemia-mediated arteriogenesis and angiogenesis. Am. J. Pathol. 169, 1886 –1898. 29. Kosaki, K., Ando, J., Korenaga, R., Kurokawa, T., Kamiya, A. (1998) Fluid shear stress increases the production of granulocyte-macrophage colony-stimulating factor by endothelial cells via mRNA stabilization. Circ. Res. 82, 794 – 802. 30. Cai, W. J., Kocsis, E., Luo, X., Schaper, W., Schaper, J. (2004) Expression of endothelial nitric oxide synthase in the vascular wall during arteriogenesis. Mol. Cell. Biochem. 264, 193–200. 31. Heil, M., Ziegelhoeffer, T., Wagner, S., Fernandez, B., Helisch, A., Martin, S., Tribulova, S., Kuziel, W. A., Bachmann, G., Schaper, W. (2004) Collateral artery growth (arteriogenesis) after experimental arterial occlusion is impaired in mice lacking CC-chemokine receptor-2. Circ. Res. 94, 671– 677. 32. Schaper, J., Konig, R., Franz, D., Schaper, W. (1976) The endothelial surface of growing coronary collateral arteries. Intimal margination and diapedesis of monocytes. A combined SEM and TEM study. Virchows Arch. A Pathol. Anat. Histol. 370, 193–205. 33. Arras, M., Ito, W. D., Scholz, D., Winkler, B., Schaper, J., Schaper, W. (1998) Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J. Clin. Invest. 101, 40 –50. 34. Grundmann, S., Hoefer, I., Ulusans, S., Bode, C., Oesterle, S., Tijssen, J. G., Piek, J. J., Buschmann, I., van Royen, N. (2006) Granulocytemacrophage colony-stimulating factor stimulates arteriogenesis in a pig model of peripheral artery disease using clinically applicable infusion pumps. J. Vasc. Surg. 43, 1263–1269. 35. Bergmann, C. E., Hoefer, I. E., Meder, B., Roth, H., van Royen, N., Breit, S. M., Jost, M. M., Aharinejad, S., Hartmann, S., Buschmann, I. R. (2006) Arteriogenesis depends on circulating monocytes and macrophage accumulation and is severely depressed in op/op mice. J. Leukoc. Biol. 80, 59 – 65. 36. Couffinhal, T., Silver, M., Kearney, M., Sullivan, A., Witzenbichler, B., Magner, M., Annex, B., Peters, K., Isner, J. M. (1999) Impaired collateral vessel development associated with reduced expression of vascular endothelial growth factor in ApoE⫺/⫺ mice. Circulation 99, 3188 –3198. 37. Stabile, E., Burnett, M. S., Watkins, C., Kinnaird, T., Bachis, A., la Sala, A., Miller, J. M., Shou, M., Epstein, S. E., Fuchs, S. (2003) Impaired arteriogenic response to acute hindlimb ischemia in CD4 – knockout mice. Circulation 108, 205–210. 38. van Weel, V., Toes, R. E., Seghers, L., Deckers, M. M., de Vries, M. R., Eilers, P. H., Sipkens, J., Schepers, A., Eefting, D., van Hinsbergh, V. W., van Bockel, J. H., Quax, P. H. (2007) Natural killer cells and CD4⫹ T-cells modulate collateral artery development. Arterioscler. Thromb. Vasc. Biol. 27, 2310 –2318. 39. Welgus, H. G., Campbell, E. J., Cury, J. D., Eisen, A. Z., Senior, R. M., Wilhelm, S. M., Goldberg, G. I. (1990) Neutral metalloproteinases produced by human mononuclear phagocytes. Enzyme profile, regulation, and expression during cellular development. J. Clin. Invest. 86, 1496 – 1502. 40. Polverini, P. J., Cotran, P. S., Gimbrone Jr., M. A., Unanue, E. R. (1977) Activated macrophages induce vascular proliferation. Nature 269, 804 – 806. 41. Cai, W., Vosschulte, R., Afsah-Hedjri, A., Koltai, S., Kocsis, E., Scholz, D., Kostin, S., Schaper, W., Schaper, J. (2000) Altered balance between extracellular proteolysis and antiproteolysis is associated with adaptive coronary arteriogenesis. J. Mol. Cell. Cardiol. 32, 997–1011. 42. Lindahl, P., Johansson, B. R., Leveen, P., Betsholtz, C. (1997) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277, 242–245. 43. Hellstrom, M., Kalen, M., Lindahl, P., Abramsson, A., Betsholtz, C. (1999) Role of PDGF-B and PDGFR-␤ in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126, 3047–3055. 44. Buschmann, I., Schaper, W. (1999) Arteriogenesis versus angiogenesis: two mechanisms of vessel growth. News Physiol. Sci. 14, 121–125. 45. Sata, M. (2006) Role of circulating vascular progenitors in angiogenesis, vascular healing, and pulmonary hypertension: lessons from animal models. Arterioscler. Thromb. Vasc. Biol. 26, 1008 –1014. 46. Song, S., Ewald, A. J., Stallcup, W., Werb, Z., Bergers, G. (2005) PDGFR␤⫹ perivascular progenitor cells in tumors regulate pericyte differentiation and vascular survival. Nat. Cell Biol. 7, 870 – 879.

10


47. Ziegelhoeffer, T., Fernandez, B., Kostin, S., Heil, M., Voswinckel, R., Helisch, A., Schaper, W. (2004) Bone marrow-derived cells do not incorporate into the adult growing vasculature. Circ. Res. 94, 230 –238. 48. Kinnaird, T., Stabile, E., Burnett, M. S., Lee, C. W., Barr, S., Fuchs, S., Epstein, S. E. (2004) Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ. Res. 94, 678 – 685. 49. Zbinden, R., Billinger, M., Seiler, C. (2004) Collateral vessel physiology and functional impact- experimental evidence of collateral behavior. Coron. Artery Dis. 15, 389 –392. 50. Pohl, T., Seiler, C., Billinger, M., Herren, E., Wustmann, K., Mehta, H., Windecker, S., Eberli, F. R., Meier, B. (2001) Frequency distribution of collateral flow and factors influencing collateral channel development. Functional collateral channel measurement in 450 patients with coronary artery disease. J. Am. Coll. Cardiol. 38, 1872–1878. 51. Fujita, M., Sasayama, S., Asanoi, H., Nakajima, H., Sakai, O., Ohno, A. (1988) Improvement of treadmill capacity and collateral circulation as a result of exercise with heparin pretreatment in patients with effort angina. Circulation 77, 1022–1029. 52. Kastrup, J., Jorgensen, E., Ruck, A., Tagil, K., Glogar, D., Ruzyllo, W., Botker, H. E., Dudek, D., Drvota, V., Hesse, B., Thuesen, L., Blomberg, P., Gyongyosi, M., Sylven, C. (2005) Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris A randomized double-blind placebo-controlled study: the Euroinject One trial. J. Am. Coll. Cardiol. 45, 982– 988. 53. Hedman, M., Hartikainen, J., Syvanne, M., Stjernvall, J., Hedman, A., Kivela, A., Vanninen, E., Mussalo, H., Kauppila, E., Simula, S., Narvanen, O., Rantala, A., Peuhkurinen, K., Nieminen, M. S., Laakso, M., Yla-Herttuala, S. (2003) Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia: phase II results of the Kuopio Angiogenesis Trial (KAT). Circulation 107, 2677–2683. 54. Grines, C. L., Watkins, M. W., Helmer, G., Penny, W., Brinker, J., Marmur, J. D., West, A., Rade, J. J., Marrott, P., Hammond, H. K., Engler, R. L. (2002) Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris. Circulation 105, 1291–1297. 55. Simons, M., Annex, B. H., Laham, R. J., Kleiman, N., Henry, T., Dauerman, H., Udelson, J. E., Gervino, E. V., Pike, M., Whitehouse, M. J., Moon, T., Chronos, N. A. (2002) Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double-blind, randomized, controlled clinical trial. Circulation 105, 788 –793. 56. Henry, T. D., Annex, B. H., McKendall, G. R., Azrin, M. A., Lopez, J. J., Giordano, F. J., Shah, P. K., Willerson, J. T., Benza, R. L., Berman, D. S., Gibson, C. M., Bajamonde, A., Rundle, A. C., Fine, J., McCluskey, E. R. (2003) The VIVA trial: Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis. Circulation 107, 1359 –1365. 57. Stewart, D. J., Hilton, J. D., Arnold, J. M., Gregoire, J., Rivard, A., Archer, S. L., Charbonneau, F., Cohen, E., Curtis, M., Buller, C. E., Mendelsohn, F. O., Dib, N,. Page, P., Ducas, J., Plante, S., Sullivan, J., Macko, J., Rasmussen, C., Kessler, P. D., Rasmussen, H. S. (2006) Angiogenic gene therapy in patients with nonrevascularizable ischemic heart disease: a phase 2 randomized, controlled trial of AdVEGF(121) (AdVEGF121) versus maximum medical treatment. Gene Ther. 13, 1503–1511. 58. Zohlnho¨fer, D., Ott, I., Mehilli, J., Schomig, K., Michalk, F., Ibrahim, T., Meisetschlager, G., von Wedel, J., Bollwein, H., Seyfarth, M., Dirschinger, J., Schmitt, C., Schwaiger, M., Kastrati, A., Schomig, A. (2006) Stem cell mobilization by granulocyte colony-stimulating factor in patients with acute myocardial infarction: a randomized controlled trial. JAMA 295, 1003–1010. 59. Seiler, C., Pohl, T., Wustmann, K., Hutter, D., Nicolet, P. A., Windecker, S., Eberli, F. R., Meier, B. (2001) Promotion of collateral growth by granulocyte-macrophage colony-stimulating factor in patients with coronary artery disease: a randomized, double-blind, placebo-controlled study. Circulation 104, 2012–2017. 60. Ripa, R. S., Jorgensen, E., Wang, Y., Thune, J. J., Nilsson, J. C., Sondergaard, L., Johnsen, H. E., Kober, L., Grande, P., Kastrup, J. (2006) Stem cell mobilization induced by subcutaneous granulocytecolony stimulating factor to improve cardiac regeneration after acute ST-elevation myocardial infarction: result of the double-blind, randomized, placebo-controlled stem cells in myocardial infarction (STEMMI) trial. Circulation 113, 1983–1992.


61. Ince, H., Petzsch, M., Kleine, H. D., Eckard, H., Rehders, T., Burska, D., Kische, S., Freund, M., Nienaber, C. A. (2005) Prevention of left ventricular remodeling with granulocyte colony-stimulating factor after acute myocardial infarction: final 1-year results of the Front-Integrated Revascularization and Stem Cell Liberation in Evolving Acute Myocardial Infarction by Granulocyte Colony-Stimulating Factor (FIRSTLINE-AMI) Trial. Circulation 112, I73–I80. 62. Erbs, S., Linke, A., Schachinger, V., Assmus, B., Thiele, H., Diederich, K. W., Hoffmann, C., Dimmeler, S., Tonn, T., Hambrecht, R., Zeiher, A. M., Schuler, G. (2007) Restoration of microvascular function in the infarct-related artery by intracoronary transplantation of bone marrow progenitor cells in patients with acute myocardial infarction: the Doppler Substudy of the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial. Circulation 116, 366 –374. 63. Janssens, S., Dubois, C., Bogaert, J., Theunissen, K., Deroose, C., Desmet, W., Kalantzi, M., Herbots, L., Sinnaeve, P., Dens, J., Maertens, J., Rademakers, F., Dymarkowski, S., Gheysens, O., Van Cleemput, J., Bormans, G., Nuyts, J., Belmans, A., Mortelmans, L., Boogaerts, M., Van de Werf, F. (2006) Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomized controlled trial. Lancet 367, 113–121. 64. Meyer, G. P., Wollert, K. C., Lotz, J., Steffens, J., Lippolt, P., Fichtner, S., Hecker, H., Schaefer, A., Arseniev, L., Hertenstein, B., Ganser, A., Drexler, H. (2006) Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months’ follow-up data from the randomized, controlled BOOST (Bone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration) trial. Circulation 113, 1287–1294. 65. Kang, H. J., Lee, H. Y., Na, S. H., Chang, S. A., Park, K. W., Kim, H. K., Kim, S. Y., Chang, H. J., Lee, W., Kang, W. J., Koo, B. K., Kim, Y. J., Lee, D. S., Sohn, D. W., Han, K. S., Oh, B. H., Park, Y. B., Kim, H. S. (2006) Differential effect of intracoronary infusion of mobilized peripheral blood stem cells by granulocyte colony-stimulating factor on left ventricular function and remodeling in patients with acute myocardial infarction versus old myocardial infarction: the MAGIC Cell-3-DES randomized, controlled trial. Circulation 114, I145–I151. 66. Scha¨chinger, V., Erbs, S., Elsasser, A., Haberbosch, W., Hambrecht, R., Holschermann, H., Yu, J., Corti, R., Mathey, D. G., Hamm, C. W., Suselbeck, T., Assmus, B., Tonn, T., Dimmeler, S., Zeiher, A. M. (2006) Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N. Engl. J. Med. 355, 1210 –1221. 67. Nikol, S., Baumgartner, I., Van Belle, E., Diehm, C., Visona, A., Capogrossi, M. C., Ferreira-Maldent, N., Gallino, A., Wyatt, M. G., Wijesinghe, L. D., Fusari, M., Stephan, D., Emmerich, J., Pompilio, G., Vermassen, F., Pham, E., Grek, V., Coleman, M., Meyer, F. (2008) Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia. Mol. Ther. 16, 972–978. 68. Makinen, K., Manninen, H., Hedman, M., Matsi, P., Mussalo, H., Alhava, E., Yla-Herttuala, S. (2002) Increased vascularity detected by digital subtraction angiography after VEGF gene transfer to human lower limb artery: a randomized, placebo-controlled, double-blinded phase II study. Mol. Ther. 6, 127–133. 69. Rajagopalan, S., Mohler III, E. R., Lederman, R. J., Mendelsohn, F. O., Saucedo, J. F., Goldman, C. K., Blebea, J., Macko, J., Kessler, P. D., Rasmussen, H. S., Annex, B. H. (2003) Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: a phase II randomized, double-blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication. Circulation 108, 1933–1938. 70. Lederman, R. J., Mendelsohn, F. O., Anderson, R. D., Saucedo, J. F., Tenaglia, A. N., Hermiller, J. B., Hillegass, W. B., Rocha-Singh, K., Moon, T. E., Whitehouse, M. J., Annex, B. H. (2002) Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomized trial. Lancet 359, 2053–2058. 71. Kusumanto, Y. H., van Weel, V., Mulder, N. H., Smit, A. J., van den Dungen, J. J., Hooymans, J. M., Sluiter, W. J., Tio, R. A., Quax, P. H., Gans, R. O., Dullaart, R. P., Hospers, G. A. (2006) Treatment with intramuscular vascular endothelial growth factor gene compared with placebo for patients with diabetes mellitus and critical limb ischemia: a double-blind randomized trial. Hum. Gene Ther. 17, 683– 691. 72. Powell, R. J., Simons, M., Mendelsohn, F. O., Daniel, G., Henry, T. D., Koga, M., Morishita, R., Annex, B. H. (2008) Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia. Circulation 118, 58 – 65.

73. van Royen, N., Schirmer, S. H., Atasever, B., Behrens, C. Y., Ubbink, D., Buschmann, E. E., Voskuil, M., Bot, P., Hoefer, I., Schlingemann, R. O., Biemond, B. J., Tijssen, J. G., Bode, C., Schaper, W., Oskam, J., Legemate, D. A., Piek, J. J., Buschmann, I. (2005) START Trial: a pilot study on STimulation of ARTeriogenesis using subcutaneous application of granulocyte-macrophage colony-stimulating factor as a new treatment for peripheral vascular disease. Circulation 112, 1040 –1046. 74. Huang, P., Li, S., Han, M., Xiao, Z., Yang, R., Han, Z. C. (2005) Autologous transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes. Diabetes Care 28, 2155–2160. 75. Tateishi-Yuyama, E., Matsubara, H., Murohara, T., Ikeda, U., Shintani, S., Masaki, H., Amano, K., Kishimoto, Y., Yoshimoto, K., Akashi, H., Shimada, K., Iwasaka, T., Imaizumi, T. (2002) Therapeutic angiogenesis for patients with limb ischemia by autologous transplantation of bonemarrow cells: a pilot study and a randomized controlled trial. Lancet 360, 427– 435. 76. Leung, D. W., Cachianes, G., Kuang, W. J., Goeddel, D. V., Ferrara, N. (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246, 1306 –1309. 77. Ferrara, N., Gerber, H. P., LeCouter, J. (2003) The biology of VEGF and its receptors. Nat. Med. 9, 669 – 676. 78. Clauss, M., Weich, H., Breier, G., Knies, U., Rockl, W., Waltenberger, J., Risau, W. (1996) The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J. Biol. Chem. 271, 17629 –17634. 79. Laramee, M., Chabot, C., Cloutier, M., Stenne, R., Holgado-Madruga, M., Wong, A. J., Royal, I. (2007) The scaffolding adapter Gab1 mediates vascular endothelial growth factor signaling and is required for endothelial cell migration and capillary formation. J. Biol. Chem. 282, 7758 – 7769. 80. Rivard, A., Silver, M., Chen, D., Kearney, M., Magner, M., Annex, B., Peters, K., Isner, J. M. (1999) Rescue of diabetes-related impairment of angiogenesis by intramuscular gene therapy with adeno-VEGF. Am. J. Pathol. 154, 355–363. 81. Mack, C. A., Magovern, C. J., Budenbender, K. T., Patel, S. R., Schwarz, E. A., Zanzonico, P., Ferris, B., Sanborn, T., Isom, P., Ferris, B., Sanborn, T., Isom, O. W., Crystal, R. G., Rosengart, T. K. (1998) Salvage angiogenesis induced by adenovirus-mediated gene transfer of vascular endothelial growth factor protects against ischemic vascular occlusion. J. Vasc. Surg. 27, 699 –709. 82. Leong-Poi, H., Kuliszewski, M. A., Lekas, M., Sibbald, M., TeichertKuliszewska, K., Klibanov, A. L., Stewart, D. J., Lindner, J. R. (2007) Therapeutic arteriogenesis by ultrasound-mediated VEGF165 plasmid gene delivery to chronically ischemic skeletal muscle. Circ. Res. 101, 295–303. 83. Greve, J. M., Chico, T. J., Goldman, H., Bunting, S., Peale Jr., F. V., Daugherty, A., van Bruggen, N., Williams, S. P. (2006) Magnetic resonance angiography reveals therapeutic enlargement of collateral vessels induced by VEGF in a murine model of peripheral arterial disease. J. Magn. Reson. Imaging 24, 1124 –1132. 84. von Degenfeld, G., Banfi, A., Springer, M. L., Wagner, R. A., Jacobi, J., Ozawa, C. R., Merchant, M. J., Cooke, J. P., Blau, H. M. (2006) Microenvironmental VEGF distribution is critical for stable and functional vessel growth in ischemia. FASEB J. 20, 2657–2659. 85. Baumgartner, I., Pieczek, A., Manor, O., Blair, R., Kearney, M., Walsh, K., Isner, J. M. (1998) Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation 97, 1114 –1123. 86. Rissanen, T. T., Yla-Herttuala, S. (2007) Current status of cardiovascular gene therapy. Mol. Ther. 15, 1233–1247. 87. van Weel, V., Deckers, M. M., Grimbergen, J. M., van Leuven, K. J., Lardenoye, J. H., Schlingemann, R. O., van Nieuw Amerongen, G. P., van Bockel, J. H., van Hinsbergh, V. W., Quax, P. H. (2004) Vascular endothelial growth factor overexpression in ischemic skeletal muscle enhances myoglobin expression in vivo. Circ. Res. 95, 58 – 66. 88. Heil, M., Clauss, M., Suzuki, K., Buschmann, I. R., Willuweit, A., Fischer, S., Schaper, W. (2000) Vascular endothelial growth factor (VEGF) stimulates monocyte migration through endothelial monolayers via increased integrin expression. Eur. J. Cell Biol. 79, 850 – 857. 89. Simons, M. (2005) Angiogenesis: where do we stand now? Circulation 111, 1556 –1566. 90. Masaki, I., Yonemitsu, Y., Yamashita, A., Sata, S., Tanii, M., Komori, K., Nakagawa, K., Hou, X., Nagai, Y., Hasegawa, M., Sugimachi, K., Sueishi, K. (2002) Angiogenic gene therapy for experimental critical limb ischemia: acceleration of limb loss by overexpression of vascular


11

91.

92.

93.

94.

95. 96.

97.

98.

99.

100.

101. 102.

103. 104.

105.

106. 107.

108.

12

endothelial growth factor 165 but not of fibroblast growth factor-2. Circ. Res. 90, 966 –973. Pipp, F., Heil, M., Issbrucker, K., Ziegelhoeffer, T., Martin, S., van den Heuvel, J., Weich, H., Fernandez, B., Golomb, G., Carmeliet, P., Schaper, W., Clauss, M. (2003) VEGFR-1-selective VEGF homologue PlGF is arteriogenic: evidence for a monocyte-mediated mechanism. Circ. Res. 92, 378 –385. Carmeliet, P., Moons, L., Luttun, A., Vincenti, V., Compernolle, V., De Mol, M., Wu, Y., Bono, F., Devy, L., Beck, H., Scholz, D., Acker, T., DiPalma, T., Dewerchin, M., Noel, A., Stalmans, I., Barra, A., Blacher, S., Vandendriessche, T., Ponten, A., Eriksson, U., Plate, K. H., Foidart, J. M., Schaper, W., Charnock-Jones, D. S., Hicklin, D. J., Herbert, J. M., Collen, D., Persico, M. G. (2001) Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat. Med. 7, 575– 583. Babiak, A., Schumm, A. M., Wangler, C., Loukas, M., Wu, J., Dombrowski, S., Matuschek, C., Kotzerke, J., Dehio, C., Waltenberger, J. (2004) Coordinated activation of VEGFR-1 and VEGFR-2 is a potent arteriogenic stimulus leading to enhancement of regional perfusion. Cardiovasc. Res. 61, 789 –795. Deindl, E., Hoefer, I. E., Fernandez, B., Barancik, M., Heil, M., Strniskova, M., Schaper, W. (2003) Involvement of the fibroblast growth factor system in adaptive and chemokine-induced arteriogenesis. Circ. Res. 92, 561–568. Yang, H. T., Deschenes, M. R., Ogilvie, R. W., Terjung, R. L. (1996) Basic fibroblast growth factor increases collateral blood flow in rats with femoral arterial ligation. Circ. Res. 79, 62– 69. Horvath, K. A., Doukas, J., Lu, C. Y., Belkind, N., Greene, R., Pierce, G. F., Fullerton, D. A. (2002) Myocardial functional recovery after fibroblast growth factor 2 gene therapy as assessed by echocardiography and magnetic resonance imaging. Ann. Thorac. Surg. 74, 481– 486. Caron, A., Michelet, S., Caron, A., Sordello, S., Ivanov, M. A., Delaere, P., Branellec, D., Schwartz, B., Emmanuel, F. (2004) Human FGF-1 gene transfer promotes the formation of collateral vessels and arterioles in ischemic muscles of hypercholesterolemic hamsters. J. Gene Med. 6, 1033–1045. Hershey, J. C., Corcoran, H. A., Baskin, E. P., Gilberto, D. B., Mao, X., Thomas, K. A., Cook, J. J. (2003) Enhanced hindlimb collateralization induced by acidic fibroblast growth factor is dependent upon femoral artery extraction. Cardiovasc. Res. 59, 997–1005. Laham, R. J., Chronos, N. A., Pike, M., Leimbach, M. E., Udelson, J. E., Pearlman, J. D., Pettigrew, R. I., Whitehouse, M. J., Yoshizawa, C., Simons, M. (2000) Intracoronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic heart disease: results of a phase I openlabel dose escalation study. J. Am. Coll. Cardiol. 36, 2132–2139. Wunsch, M., Sharma, H. S., Markert, T., Bernotat-Danielowski, S., Schott, R. J., Kremer, P., Bleese, N., Schaper, W. (1991) In situ localization of transforming growth factor ␤ 1 in porcine heart: enhanced expression after chronic coronary artery constriction. J. Mol. Cell. Cardiol. 23, 1051–1062. Conway, E. M., Collen, D., Carmeliet, P. (2001) Molecular mechanisms of blood vessel growth. Cardiovasc. Res. 49, 507–521. van Royen, N., Hoefer, I., Buschmann, I., Heil, M., Kostin, S., Deindl, E., Vogel, S., Korff, T., Augustin, H., Bode, C., Piek, J. J., Schaper, W. (2002) Exogenous application of transforming growth factor ␤ 1 stimulates arteriogenesis in the peripheral circulation. FASEB J. 16, 432– 434. Singh, N. N., Ramji, D. P. (2006) The role of transforming growth factor-␤ in atherosclerosis. Cytokine Growth Factor Rev. 17, 487– 499. Lutgens, E., Gijbels, M., Smook, M., Heeringa, P., Gotwals, P., Koteliansky, V. E., Daemen, M. J. (2002) Transforming growth factor-␤ mediates balance between inflammation and fibrosis during plaque progression. Arterioscler. Thromb. Vasc. Biol. 22, 975–982. Grundmann, S., van Royen, N., Pasterkamp, G., Gonzalez, N., Tijsma, E. J., Piek, J. J., Hoefer, I. E. (2007) A new intra-arterial delivery platform for pro-arteriogenic compounds to stimulate collateral artery growth via transforming growth factor-␤1 release. J. Am. Coll. Cardiol. 50, 351–358. Shireman, P. K. (2007) The chemokine system in arteriogenesis and hind limb ischemia. J. Vasc. Surg. 45 (Suppl. A), A48 –A56. Wang, D. L., Wung, B. S., Shyy, Y. J., Lin, C. F., Chao, Y. J., Usami, S., Chien, S. (1995) Mechanical strain induces monocyte chemotactic protein-1 gene expression in endothelial cells. Effects of mechanical strain on monocyte adhesion to endothelial cells. Circ. Res. 77, 294 –302. Voskuil, M., Hoefer, I. E., van Royen, N., Hua, J., de Graaf, S., Bode, C., Buschmann, I. R., Piek, J. J. (2004) Abnormal monocyte recruitment and


109. 110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

collateral artery formation in monocyte chemoattractant protein-1 deficient mice. Vasc. Med. 9, 287–292. Tang, G., Charo, D. N., Wang, R., Charo, I. F., Messina, L. (2004) CCR2⫺/⫺ knockout mice revascularize normally in response to severe hindlimb ischemia. J. Vasc. Surg. 40, 786 –795. Namiki, M., Kawashima, S., Yamashita, T., Ozaki, M., Hirase, T., Ishida, T., Inoue, N., Hirata, K., Matsukawa, A., Morishita, R., Kaneda, Y., Yokoyama, M. (2002) Local overexpression of monocyte chemoattractant protein-1 at vessel wall induces infiltration of macrophages and formation of atherosclerotic lesion: synergism with hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol. 22, 115–120. van Royen, N., Hoefer, I., Bottinger, M., Hua, J., Grundmann, S., Voskuil, M., Bode, C., Schaper, W., Buschmann, I., Piek, J. J. (2003) Local monocyte chemoattractant protein-1 therapy increases collateral artery formation in apolipoprotein E-deficient mice but induces systemic monocytic CD11b expression, neointimal formation, and plaque progression. Circ. Res. 92, 218 –225. van Weel, V., de Vries, M., Voshol, P. J., Verloop, R. E., Eilers, P. H., van Hinsbergh, V. W., van Bockel, J. H., Quax, P. H. (2006) Hypercholesterolemia reduces collateral artery growth more dominantly than hyperglycemia or insulin resistance in mice. Arterioscler. Thromb. Vasc. Biol. 26, 1383–1390. Buschmann, I. R., Hoefer, I. E., van Royen, N., Katzer, E., BraunDulleaus, R., Heil, M., Kostin, S., Bode, C., Schaper, W. (2001) GMCSF: a strong arteriogenic factor acting by amplification of monocyte function. Atherosclerosis 159, 343–356. Buschmann, I. R., Busch, H. J., Mies, G., Hossmann, K. A. (2003) Therapeutic induction of arteriogenesis in hypoperfused rat brain via granulocyte-macrophage colony-stimulating factor. Circulation 108, 610 – 615. Inoue, I., Inaba, T., Motoyoshi, K., Harada, K., Shimano, H., Kawamura, M., Gotoda, T., Oka, T., Shiomi, M., Watanabe, Y., et al. (1992) Macrophage colony stimulating factor prevents the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbits. Atherosclerosis 93, 245–254. Ishibashi, T., Yokoyama, K., Shindo, J., Hamazaki, Y., Endo, Y., Sato, T., Takahashi, S., Kawarabayasi, Y., Shiomi, M., Yamamoto, T., et al. (1994) Potent cholesterol-lowering effect by human granulocyte-macrophage colony-stimulating factor in rabbits. Possible implications of enhancement of macrophage functions and an increase in mRNA for VLDL receptor. Arterioscler. Thromb. 14, 1534 –1541. Zbinden, S., Zbinden, R., Meier, P., Windecker, S., Seiler, C. (2005) Safety and efficacy of subcutaneous-only granulocyte-macrophage colonystimulating factor for collateral growth promotion in patients with coronary artery disease. J. Am. Coll. Cardiol. 46, 1636 –1642. Iwanaga, K., Takano, H., Ohtsuka, M., Hasegawa, H., Zou, Y., Qin, Y., Odaka, K., Hiroshima, K., Tadokoro, H., Komuro, I. (2004) Effects of G-CSF on cardiac remodeling after acute myocardial infarction in swine. Biochem. Biophys. Res. Commun. 325, 1353–1359. Orlic, D., Kajstura, J., Chimenti, S., Limana, F., Jakoniuk, I., Quaini, F., Nadal-Ginard, B., Bodine, D. M., Leri, A., Anversa, P. (2001) Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc. Natl. Acad. Sci. USA 98, 10344 –10349. Kocher, A. A., Schuster, M. D., Szabolcs, M. J., Takuma, S., Burkhoff, D., Wang, J., Homma, S., Edwards, N. M., Itescu, S. (2001) Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat. Med. 7, 430 – 436. Deindl, E., Zaruba, M. M., Brunner, S., Huber, B., Mehl, U., Assmann, G., Hoefer, I. E., Mueller-Hoecker, J., Franz, W. M. (2006) G-CSF administration after myocardial infarction in mice attenuates late ischemic cardiomyopathy by enhanced arteriogenesis. FASEB J. 20, 956 – 958. Hill, J. M., Syed, M. A., Arai, A. E., Powell, T. M., Paul, J. D., Zalos, G., Read, E. J., Khuu, H. M., Leitman, S. F., Horne, M., Csako, G., Dunbar, C. E., Waclawiw, M. A., Cannon, R. O. (2005) Outcomes and risks of granulocyte colony-stimulating factor in patients with coronary artery disease. J. Am. Coll. Cardiol. 46, 1643–1648. Schachinger, V., Erbs, S., Elsasser, A., Haberbosch, W., Hambrecht, R., Holschermann, H., Yu, J., Corti, R., Mathey, D. G., Hamm, C. W., Suselbeck, T., Werner, H., Haase, J., Neuzner, J., Germing, A., Mark, B., Assmus, B., Tonn, T., Dimmeler, S., Zeiher, A. M. (2006) Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur. Heart J. 27, 2775–2783. Abdel-Latif, A., Bolli, R., Tleyjeh, I. M., Montori, V. M., Perin, E. C., Hornung, C. A., Zuba-Surma, E. K., Al-Mallah, M., Dawn, B. (2007)


125.

126.

127.

128.

129.

130.

Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Arch. Intern. Med. 167, 989 –997. Lipinski, M. J., Biondi-Zoccai, G. G., Abbate, A., Khianey, R., Sheiban, I., Bartunek, J., Vanderheyden, M., Kim, H. S., Kang, H. J., Strauer, B. E., Vetrovec, G. W. (2007) Impact of intracoronary cell therapy on left ventricular function in the setting of acute myocardial infarction: a collaborative systematic review and meta-analysis of controlled clinical trials. J. Am. Coll. Cardiol. 50, 1761–1767. Van Tongeren, R. B., Hamming, J. F., Fibbe, W. E., Van Weel, V., Frerichs, S. J., Stiggelbout, A. M., Van Bockel, J. H., Lindeman, J. H. (2008) Intramuscular or combined intramuscular/intra-arterial administration of bone marrow mononuclear cells: a clinical trial in patients with advanced limb ischemia. J. Cardiovasc. Surg. (Torino) 49, 51–58. Sprengers, R. W., Lips, D. J., Moll, F. L., Verhaar, M. C. (2008) Progenitor cell therapy in patients with critical limb ischemia without surgical options. Ann. Surg. 247, 411– 420. Herold, J., Pipp, F., Fernandez, B., Xing, Z., Heil, M., Tillmanns, H., Braun-Dullaeus, R. C. (2004) Transplantation of monocytes: a novel strategy for in vivo augmentation of collateral vessel growth. Hum. Gene Ther. 15, 1–12. Andreesen, R., Scheibenbogen, C., Brugger, W., Krause, S., Meerpohl, H. G., Leser, H. G., Engler, H., Lohr, G. W. (1990) Adoptive transfer of tumor cytotoxic macrophages generated in vitro from circulating blood monocytes: a new approach to cancer immunotherapy. Cancer Res. 50, 7450 –7456. Abaci, A., Oguzhan, A., Kahraman, S., Eryol, N. K., Unal, S., Arinc, H., Ergin, A. (1999) Effect of diabetes mellitus on formation of coronary collateral vessels. Circulation 99, 2239 –2242.

131. Waltenberger, J. (2001) Impaired collateral vessel development in diabetes: potential cellular mechanisms and therapeutic implications. Cardiovasc. Res. 49, 554 –560. 132. Czepluch, F. S., Bergler, A., Waltenberger, J. (2007) Hypercholesterolemia impairs monocyte function in CAD patients. J. Intern. Med. 261, 201–204. 133. Tirziu, D., Moodie, K. L., Zhuang, Z. W., Singer, K., Helisch, A., Dunn, J. F., Li, W., Singh, J., Simons, M. (2005) Delayed arteriogenesis in hypercholesterolemic mice. Circulation 112, 2501–2509. 134. Kornowski, R. (2003) Collateral formation and clinical variables in obstructive coronary artery disease: the influence of hypercholesterolemia and diabetes mellitus. Coron. Artery Dis. 14, 61– 64. 135. Hochberg, I., Roguin, A., Nikolsky, E., Chanderashekhar, P. V., Cohen, S., Levy, A. P. (2002) Haptoglobin phenotype and coronary artery collaterals in diabetic patients. Atherosclerosis 161, 441– 446. 136. Gulec, S., Karabulut, H., Ozdemir, A. O., Ozdol, C., Turhan, S., Altin, T., Tutar, E., Genc, Y., Erol, C. (2008) Glu298Asp polymorphism of the eNOS gene is associated with coronary collateral development. Atherosclerosis 198, 354 –359. 137. Chittenden, T. W., Sherman, J. A., Xiong, F., Hall, A. E., Lanahan, A. A., Taylor, J. M., Duan, H., Pearlman, J. D., Moore, J. H., Schwartz, S. M., Simons, M. (2006) Transcriptional profiling in coronary artery disease: indications for novel markers of coronary collateralization. Circulation 114, 1811–1820. 138. Schirmer, S. H., Fledderus, J. O., Bot, P., Moerland, P. D., Hoefer, I., Baan, J., Henriques, J. P. S., van der Schaaf, R. J., Vis, M. M., Horrevoets, A. J., Piek, J. J., Van Royen, N. (2008) Interferon-␤ signaling is enhanced in patients with insufficient coronary collateral artery development and inhibits arteriogenesis in mice. Circ. Res. 102, 1286 – 1294.


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