Circulation Research. 2001;89:678-683
Published online before print September 27, 2001, doi: 10.1161/hh2001.097691
Published online before print September 27, 2001, doi: 10.1161/hh2001.097691
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© 2001 American Heart Association, Inc.
Molecular Medicine |
Proangiogenic Effect of Angiotensin-Converting Enzyme Inhibition Is Mediated by the Bradykinin B2 Receptor Pathway
From INSERM U541, Hôpital Lariboisière, Institut Fédératif de Recherche Circulation-Paris 7, Université Paris 7-Denis Diderot, Paris, France.
Correspondance to Bernard I. Levy, U541-INSERM, Hôpital Lariboisière, 41 Bd de la Chapelle, 75475 Paris cedex 10, France. E-mail levy{at}infobiogen.fr
Abstract—— Recent studies have suggested a proangiogenic effect of angiotensin-converting enzyme (ACE) inhibition. We hypothesized that such a proangiogenic effect of ACE inhibition may be mediated, in part, by bradykinin (BK) B2-receptor pathway. This study therefore examined the neovascularization induced by ACE inhibitor treatment in B2 receptor–deficient mice (B2-/-) in a model of surgically induced hindlimb ischemia. After artery femoral occlusion, wild-type and B2-/- mice were treated with or without ACE inhibitor (perindopril, 3 mg/kg/d) for 28 days. Angiogenesis was then quantitated by microangiography, capillary density measurement, and laser Doppler perfusion imaging. The protein levels of vascular endothelial growth factor (VEGF) and 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 ACE inhibitor when compared with the nontreated animals (P<0.01). This corresponded 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 angiogenic process was also associated with a 1.7-fold increase in tissue eNOS protein level in mice treated with ACE inhibitor (P<0.05 versus control) but not with changes in VEGF protein level. Conversely, ACE inhibition did not affect vessel density, blood flow, and eNOS protein level in ischemic hindlimb of B2-/- mice. Therefore, proangiogenic effect of ACE inhibition is mediated by B2-receptor signaling and was associated with upregulation of eNOS content, independently of VEGF expression.
Key Words: angiogenesis • ischemia • kinins • angiotensin-converting enzyme • B2 receptor
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