manipulating kinin signaling to promote neovascularization

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Helping the circulatory system heal itself: manipulating kinin signaling to promote neovascularization Expert Rev. Cardiovasc. Ther. 7(3), 215–219 (2009)

Nicolle Kränkel, PhD Postdoctoral Fellow at the Chair of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Level 7, Upper Maudlin Street, Bristol BS2 8HW, UK Tel.: +44 117 928 3151 [email protected]

Paolo Madeddu, MD CS FAHA Author for correspondence

Professor, and Chair of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Level 7, Upper Maudlin Street, Bristol BS2 8HW, UK Tel.: +44 117 928 3904 Fax: +44 117 928 3904 [email protected]

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“The kallikrein–kinin system ... is emerging as a therapeutic target for maintaining vascular function and integrity, as well as promoting the growth of new blood vessels.” Maintaining vessel integrity and mounting a fast revascularization response after an ischemic event represent desirable yet unmet goals in current cardiovascular prevention and therapy. The kallikrein– kinin system (KKS) – originally identified to participate in the control of blood pressure – is emerging as a therapeutic target for maintaining vascular function and integrity, as well as promoting the growth of new blood vessels. The KKS is a complex signaling network, initiated by kinin generation from kininogens through kallikreins. Downstream, kininases process kinins (namely, kallidin and bradykinin) into inactive peptides or kinin metabolites (des-Arg-kallidin, desArg-bradykinin). Both kinins and kinin metabolites exert their effects through distinct receptors, the kinin B2 (B2R) and B1 (B1R) receptors, respectively. Kallikrein can activate the B2R via generation of kinins and also in a kinin-independent, direct way , inducing anti-apoptotic signaling pathways including protein kinase Akt, endothelial nitric oxide (NO) synthase, and glycogen synthase kinase 3 [1–4] . B1R signaling, on the other hand, mainly activates NF-κB (along with the production of inflammatory cytokines and collagen) and p38-MAPK (followed by caspase activation) [5,6] . Nevertheless, both kinin receptors have been shown to be involved in angio genesis, although involvement of the B1R was highly dependent on the pathological circumstances, especially the persistence of inflammation [7–13] . In a recent study, Sanchez de Miguel et al. found the B2R to be essential for bradykinin-induced vessel

10.1586/14779072.7.3.215

sprouting from cardiac explants, while the B1R was involved only to a minor extent [13] . Furthermore, the authors verified the earlier finding that the B2R is involved in the transmission of VEGF signals, underlining the role of this receptor as a nexus for proangiogenic cellular signaling [13,14] . Viral overexpression of the B2R has therefore been postulated as a rescue strategy in conditions of impaired angiogenesis [15] . Unfortunately, only few data exist on the effects of B2R overexpression in vitro, and its use for the rescue of angiogenesis in models of cardiovascular disease or diabetes – the main target groups for proangiogenic treatment – has not been attempted so far. In light of earlier findings indicating that the bottleneck of proangiogenic signaling is located downstream of the receptor level [16] , it might be necessary to address several steps of the cascade simultaneously, such as providing exogenous NO together with B2R overexpression. Apart from kinin generation, kallikreins can promote vessel growth by kinin-independent mechanisms. Direct activation of the B2R by kallikrein, bypassing kinin generation, has recently been shown [2] . Furthermore, through cleavage of extracellular matrix proteins, as well as activation of other matrix proteases, for example gelatinases, kallikrein might facilitate the detachment of resident mature endothelial cells (ECs) from the matrix, a preceding step to EC migration and subsequent vessel sprouting [17,18] . Cleavage and activation of growth factors, such as HGF and IGF, as well as matrix metalloproteases, which in turn modulate growth factor and cytokine

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activity, might contribute to EC survival and migration [19–24] . Consistent with its aforementioned pleiotropic effects, local overexpression of the human tissue kallikrein gene (KLK1) in ischemic tissues led to faster revascularization via a multitude of mechanisms, the most prominent of which seems to be mediated by the B2R [4,8,25,26] . Concerns regarding the safety of viral gene overexpression for therapeutic purposes in humans have prevented translation of those findings for a long time. However, with the development of safer gene-delivery strategies [27–30] , KLK1 over expression might be considered a therapeutic option in the future. In the meantime, infusion of recombinant kallikrein might represent an alternative [31,32] . Yet, for distinct patient populations, benefit from kallikrein supplementation might be limited. While in Type 1 diabetes adenoviral KLK1 overexpression was able to rescue capillarization and blood flow in ischemic hindlimbs, we previously found that in a Type 2 diabetes model KLK1 improved capillarization but not blood flow recovery [33,34] .

“Unfortunately, only few data exist on the effects of B2R overexpression in vitro, and its use for the rescue of angiogenesis in models of cardiovascular disease or diabetes – the main target groups for proangiogenic treatment – has not been attempted so far.” Subject to enzymatic degradation by angiotensin-converting enzyme (ACE), neutral endopeptidase and carboxypeptidases, kinins have a short half-life in the blood [35] . Modulation of kininase expression and activity has been reported in several vascular pathologies [36–39] . Consequently, inhibition of ACE enhances kinin stability and promotes vascular sprouting in animal models as well as in human cardiovascular patients, partly via the B2R and partly via other mechanisms [13,9,40–42] . Using angio tensin II receptor type 1 knockout mice, Li et al. demonstrated the involvement of both kinin receptors and NO signaling in ACE inhibitor-mediated angiogenesis in hindlimb ischemia [9] . Interestingly, the proangiogenic effect of ACE inhibition was blocked to a greater extent by the B2R antagonist HOE140 than by B1R antagonism [9] . In contrast to limb or myocardial vascularization, studies investigating the effect of ACE inhibition on neovascularization in the eye deliver conflicting results. Ebrahimian et al., directly comparing capillarization in hindlimb and retina in Type 1 diabetic mice, report a positive effect of ACE inhibition in the leg, but a reduction of vessel growth in the eye [43] . In nondiabetic wild-type or angiotensin II receptor type 1-deficient mice, on the other hand, Nagai et al. describe ACE inhibition-mediated vessel growth, albeit via a B2R-independent mechanism. However, B1R involvement was not studied, leaving the authors to speculate on involvement of renin–angiotensin-mediated effects [44] . Fewer studies have been performed to evaluate the benefit of inhibiting neutral endopeptidase, the major bradykinin-degrading enzyme in the heart [45,46] . A proangiogenic effect is indicated by 216

studies reporting faster cancer progression to be associated with increased tumor vascularization under neutral endopeptidase inhibition [47,48] . Again, further studies in relevant models are necessary to understand the therapeutic potential for kininase blockers in vascularization of cardiovascular patients with and without diabetes. Over the last decade, the role of circulating cells in postnatal vascularization has been a field of intense study. Apart from monocytes, which are known to be implicated in the mounting stage of angiogenesis, a small portion of circulating cells consists of immature progenitors, which after homing to ischemic tissue are able to differentiate into cells of the vessel wall, thus contributing to in situ vessel generation (vasculogenesis) [49–52] . The exact definition of those endothelial progenitor cells (EPCs) is still debated and parallel characterization methods result in heterogeneous results. However, it seems clear at the moment that two major populations of proangiogenic cells can be enriched by culturebased methods from the circulation: a rare population of cells, which adheres to collagen fast (within 24 h) and results in a late outgrowth (after 2–3 weeks) of endothelial colonies (termed ‘late EPC’), as well as a larger population, which adhere to fibronectin after 2 days but soon yield colonies (termed ‘early EPC’). The former give rise to endothelial-like cells, while the latter consist mainly of monocytic cells whose proangiogenic effect largely relies on paracrine mechanisms, namely, the secretion of growth factors and cytokines that promote EC survival, proliferation and migration [51,53] . The capacity of kallikrein to activate matrix metallopeptidase (MMP)-9 suggests its implication in EPC release from the bone marrow [54–56] . Indeed, in KLK1-deficient mice, we recently described a reduced number of circulating lin-cKit+ cells, as compared with wild-type controls, associated with a reduced amount of capillary formation in ischemic muscles [57] . Vice versa, adenoviral KLK1 gene delivery promoted capillarization and blowflow recovery in ischemic limbs, as we and others have repeatedly shown [8,10,25,26,32,58,59] . In MMP9-deficient mice, however, KLK1 overexpression was inefficient [57] . The extent and exact mechanisms of MMP9-involvement in kallikrein-induced EPC release are still unresolved at present. Further to their availability in the circulation, the capacity of EPCs to home to ischemic tissue is a prerequisite to their pro angiogenic action. We recently reported that bradykinin can serve as a chemoattractant for circulating EPCs [60] . In this study, B2R-mediated recruitment of proangiogenic, circulating cells to ischemic tissues was crucial to neovascularization [60] . Different cytokine secretion profiles of bradykinin-responsive and -non responsive cells, along with the ubiquitously low number of incorporating donor cells in all study groups, points again towards a paracrine mechanism of EPC-mediated neovessel formation [60] . Furthermore, cultured ‘early EPC’ produced NO – a crucial pro angiogenic factor – upon stimulation with bradykinin. This opens up the possibility of ex vivo modification of a patient’s EPC or bone marrow cells before reinjection – specifically with respect to their secretory activity. KLK1 overexpression in EPCs from cardiovascular patients prior to re-injection may therefore provide Expert Rev. Cardiovasc. Ther. 7(3), (2009)

Manipulating kinin signaling to promote neovascularization

a strategy to exploit and support EPC paracrine action, as well as to overcome limited homing and invasive potential of the patient’s EPCs. Although it has not been studied before, encouraging data exist from a study employing mesenchymal stem cells as vehicles for KLK1 overexpression in a model of kidney healing after acute ischemia/reperfusion [61] . The authors report reduced inflammation and apoptosis along with increased Akt activation and an overall protective effect against ischemia/reperfusion damage [61] . Preliminary data from our own group indeed suggest a higher invasive potential of KLK1-overexpressing cultured early EPCs, as well as increased blood-flow recovery of ischemic hindlimbs, when KLK1-transfected EPCs were transplanted instead of EPCs transfected with empty vector [62] . Another problem to solve for routine application of autologous stem/progenitor cells for vascular regeneration consists of the composition of the transplanted cell population. Although bone marrow cells harbor a high number of stem/progenitor cells with regenerative potential, the majority consists of hematopoietic and mesenchymal stem/progenitor cells, which each might exert their own, perhaps unwanted, effects. As previous studies have shown, transplanted cell function strongly depends on milieu conditions [63,64] , which are usually proinflammatory/profibrotic in cardiovascular patients. The anti-inflammatory and antifibrotic effects of kallikrein would again recommend genetic manipulation of transplanted cells (i.e., KLK1 overexpression). An alternative approach consists of the selection and transplantation of functional effector cells from the background of dysfunctional or unwanted cells. We have shown that it is possible to enrich EPCs and other cells with in vitro proangiogenic effects from total peripheral blood leukocytes by migration towards bradykinin [60] . In vitro, the migrating cells exhibit a more proangiogenic cytokine profile, while non-migrating cells secreted higher amounts of inflammatory cytokines, such as RANTES. Interestingly, enrichment of proangiogenic cells was still possible from the blood of patients within the first 3 days after acute myocardial infarction with functional capacity of the enriched cells comparable to those obtained from healthy controls. By contrast, cells derived from patients with stable angina exhibited a severely reduced capacity to be enriched by bradykinin and the enriched cells did not stimulate in vitro angiogenesis [60] . Although initial data indicate a restriction of the suitability of this function-based cell enrichment method to only a selected patient cohort, it opens up a new strategy to select for References 1

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cells with a specific functional response. Further studies will need to investigate this approach in more detail, for example by modulating the type of chemoattractant used or by applying the reverse principle, depleting for cells attracted by antiangiogenic cytokines (e.g., RANTES). However, a lot of work needs to be completed in order to define the most effective population for therapeutic angiogenesis and for finetuning their function. While it seems appealing to use specifically manipulated endogenous cells to target the desirable effect, thereby limiting side-effects, the feasibility of this approach still needs to be determined. Seminal studies have demonstrated a poor longterm persistence of injected cells in the target tissue and systemically injected cells home even less efficiently, mostly being retained in the spleen. Moreover, while ex vivo manipulated cells might possess an improved functional capacity – such as the secretion of growth factors – their targets and actual effectors of angiogenesis (EC) might be unable to respond owing to their own dysfunction. Taken together, the multiple pathways interlinking within the KKS – kinin generation by kallikreins and degradation by kininases, kinin receptor expression and function, and kininindependent actions of kallikrein – offer the possibility of tackling different steps within KKS proangiogenic signaling, rather than just interfering with one point of the cascade. Apart from pharm acological approaches, transgenic options move into the range of feasibility with the development of safer viruses and with the use of endogenous cells as gene carriers. Combined approaches, such as inhibition of kininases together with increasing kinin supply by providing exogenous kallikrein, as well as modulation of B1 versus B2 receptor signaling, need to be tailored specifically for distinct patient cohorts. Finally, selection of functional cell populations as well as ex vivo ‘pampering’ of autologous cells prior to transplantation might help to overcome deficiencies of patient-derived stem cells. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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