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
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.