Angiogenesis and angiotensin II: differential postnatal angiogenic activities unmasked by gene-engineered mouse models of angiotensin AT1 and AT2 receptor subtypes

We tested angiogenic activities of angiotensin II(Ang II) in ischemic hindlimbs using AT1 receptor(AT1R)-knock out(KO), AT2R-KO, wild-type(WT) mice. METHODS AND RESULTS: Angiogenesis was evaluated three weeks after unilateral hindlimb ischemia by laser Doppler perfusion(LDP) and capillary density. The ischemia/normal LDP ratio was markedly(p < 0.001) decreased in AT1R-KO(54 +/- 5% recovery) and AngII infusion-AT1R-KO(43 +/- 3%) than in WT(71 +/- 6%). In contrast, ischemia/normal LDP ratio was significantly(p < 0.01) increased in AT2R-KO(82 +/- 5%) and AngII infusion-AT2R-KO(96 +/- 6%) than in WT(71 +/- 6%). AT1R-KO and AngII infusion -AT1R-KO mice displayed lower capillary densities than WT(15 +/- 3, 11 +/- 3 vs 24 +/- 3 per field; p < 0.001). CONCLUSION: Ischemia in skeletal muscle causes upregulation of AT1R and AT2R expression, which positively and negatively modulates VEGF expression. This VEGF regulation via AngII receptor subtypes is closely involved in postnatal angiogenesis in ischemic limbs.