Proangiogenic effect of angiotensin-converting enzyme inhibition is mediated by the bradykinin B-2 receptor pathway

Citation
Js. Silvestre et al., Proangiogenic effect of angiotensin-converting enzyme inhibition is mediated by the bradykinin B-2 receptor pathway, CIRCUL RES, 89(8), 2001, pp. 678-683
Citations number
26
Categorie Soggetti
Cardiovascular & Hematology Research
Journal title
CIRCULATION RESEARCH
ISSN journal
00097330 → ACNP
Volume
89
Issue
8
Year of publication
2001
Pages
678 - 683
Database
ISI
SICI code
0009-7330(20011012)89:8<678:PEOAEI>2.0.ZU;2-N
Abstract
Recent studies have suggested a proangiogenic effect of angiotensin-convert ing enzyme (ACE) inhibition. We hypothesized that such a proangiogenic effe ct of ACE inhibition may be mediated, in part, by bradykinin (BK) B-2-recep tor pathway. This study therefore examined the neovascularization induced b y ACE inhibitor treatment in B-2 receptor-deficient mice (B-2(-/-)) in a mo del of surgically induced hindlimb ischemia. After artery femoral occlusion , wild-type and B-2(-/-) mice were treated with or without ACE inhibitor (p erindopril, 3 mg/kg/d) for 28 days. Angiogenesis was then quantitated by mi croangiography, capillary density measurement, and laser Doppler perfusion imaging. The protein levels of vascular endothelial growth factor (VEGF) an d endothelial nitric oxide synthase (eNOS) were determined by Western blot. In wild-type animals, vessel density and capillary number in the ischemic leg were raised by 1.8- and 1.4-fold, respectively, in mice treated with AC E inhibitor when compared with the nontreated animals (P <0.01). This corre sponded to an improved ischemic/nonischemic leg perfusion ratio by 1.5-fold in ACE inhibitor-treated animals when compared with the untreated ones (0. 87 +/-0.07 versus 0.59 +/-0.05, respectively, P <0.01). Activation of the a ngiogenic process was also associated with a 1.7-fold increase in tissue eN OS protein level in mice treated with ACE inhibitor (P <0.05 versus control ) but not with changes in VEGF protein level. Conversely, ACE inhibition di d not affect vessel density, blood flow, and eNOS protein level in ischemic hindlimb of B-2(-/-) mice. Therefore, proangiogenic effect of ACE inhibiti on is mediated by B-2-receptor signaling and was associated with upregulati on of eNOS content, independently of VEGF expression.