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Angiotensin AT(1) receptor signalling modulates reparative angiogenesis induced by limb ischaemia.

ABSTRACT: 1. The concept that angiotensin II exerts pro-angiogenic activity is not universally accepted. We evaluated whether inhibition of the renin-angiotensin system (RAS) would influence reparative angiogenesis in a murine model of limb ischaemia. 2. Perfusion recovery following surgical removal of the left femoral artery was analysed by laser Doppler flowmetry in mice given the ACE inhibitor ramipril (1 mg kg(-1) per day), the AT(1) antagonist losartan (15 mg kg(-1) per day), or vehicle. Muscular capillarity was examined at necroscopy. Ramipril-induced effects were also studied under combined blockade of kinin B(1) and B(2) receptors. Furthermore, the effects of ischaemia on AT(1) gene expression and ACE activity were determined. 3. In untreated mice, muscular AT(1a) gene expression was transiently decreased early after induction of limb ischaemia, whereas AT(1b) mRNA was up-regulated. ACE activity was reduced in ischaemic muscles at 1 and 3 days. Gene expression of AT(1) isoforms as well as ACE activity returned to basal values by day 14. Spontaneous neovascularization allowed for complete perfusion recovery of the ischaemic limb after 21 days. 4. Reparative angiogenesis was negatively influenced by either ramipril (P<0.02) or losartan (P<0.01), leading to delayed and impaired post-ischaemic recovery (50 - 70% less compared with controls). Ramipril-induced effects remained unaltered under kinin receptor blockade. 5. The present study indicates that (a) expression of angiotensin II AT(1) receptors and ACE activity are modulated by ischaemia, (b) ACE-inhibition or AT(1) antagonism impairs reparative angiogenesis, and (c) intact AT(1) receptor signalling is essential for post-ischaemic recovery. These results provide new insights into the role of the RAS in vascular biology and suggest cautionary use of ACE inhibitors and AT(1) antagonists in patients at risk for developing peripheral ischaemia.

SUBMITTER: Emanueli C

PROVIDER: S-EPMC1573122 | biostudies-other | 2002 Jan

REPOSITORIES: biostudies-other

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Project description:Background Circadian rhythm disorders, often seen in modern lifestyles, are a major social health concern. The aim of this study was to examine whether circadian rhythm disorders would influence angiogenesis and blood perfusion recovery in a mouse model of hind limb ischemia. Methods and Results A jet-lag model was established in C57BL/6J mice using a light-controlled isolation box. Control mice were kept at a light/dark 12:12 (12-hour light and 12-hour dark) condition. Concentrations of plasma vascular endothelial growth factor and circulating endothelial progenitor cells in control mice formed a circadian rhythm, which was diminished in the jet-lag model (P<0.05). The jet-lag condition deteriorated tissue capillary formation (P<0.001) and tissue blood perfusion recovery (P<0.01) in hind limb ischemia, which was associated with downregulation of vascular endothelial growth factor expression in local ischemic tissue and in the plasma. Although the expression of clock genes (ie, Clock, Bmal1, and Cry) in local tissues was upregulated after ischemic injury, the expression levels of cryptochrome (Cry) 1 and Cry2 were inhibited by the jet-lag condition. Next, Cry1 and Cry2 double-knockout mice were examined for blood perfusion recoveries and a reparative angiogenesis. Cry1 and Cry2 double-knockout mice revealed suppressed capillary density (P<0.001) and suppressed tissue blood perfusion recovery (P<0.05) in the hind limb ischemia model. Moreover, knockdown of CRY1/2 in human umbilical vein endothelial cells was accompanied by increased expression of WEE1 and decreased expression of HOXC5. This was associated with decreased proliferative capacity, migration ability, and tube formation ability of human umbilical vein endothelial cells, respectively, leading to impairment of angiogenesis. Conclusions Our data suggest that circadian rhythm disorder deteriorates reparative ischemia-induced angiogenesis and that maintenance of circadian rhythm plays an important role in angiogenesis.

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Angiotensin AT(1) receptor signalling modulates reparative angiogenesis induced by limb ischaemia.

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