doi: 10.1161/hy0302.104671
(Hypertension. 2002;39:830.)
© 2002 American Heart Association, Inc.
Scientific Contributions |
Endothelial Nitric Oxide Synthase Lies Downstream From Angiotensin II–Induced Angiogenesis in Ischemic Hindlimb
From INSERM U541, Hôpital Lariboisière, IFR Circulation-Paris 7, Université Paris 7-Denis Diderot (R.T., J-S.S., N.K., J.B., M.D., D.H., B.I.L.), Paris, France; and Novartis Pharma AG (M.d.G.), Basel, Switzerland.
Correspondence to Bernard I. Levy, U541-INSERM, Hôpital Lariboisière, 41 Bd de la Chapelle, 75475 Paris cedex 10, France. E-mail levy@ infobiogen.fr
We assessed the role of angiotensin (Ang) II in ischemia-induced angiogenesis and analyzed the molecular pathways involved in such an effect. Ischemia was produced by unilateral artery femoral occlusion in control, in valsartan-treated (Ang II receptor type I antagonist, 20 mg/kg per day), in Ang II–treated (5 ng/kg per min), and in Ang II and valsartan–treated rats. After 28 days, angiogenesis was assessed by microangiography and capillary density measurement in hindlimbs. The ischemic/nonischemic leg ratio for angiographic score and capillary number increased by 2.6- and 2-fold, respectively, in Ang II–treated rats compared with controls (P<0.01). This was associated with an increase in vascular endothelial growth factor (VEGF; 1.6-fold) and endothelial NO synthase (eNOS; 1.8-fold) protein content within the ischemic leg, assessed by Western blot. Angiotensin type 1 receptor blockade and administration of VEGF neutralizing antibody (2.5 µg IP, twice a week) in Ang II–treated rats completely prevented such Ang II angiogenic effects. The key role of eNOS was then emphasized by using mice deficient in gene encoding for eNOS. In wild-type mice, Ang II (0.3 mg/kg per min) treatment increased by 1.7- and 1.6-fold the ischemic/nonischemic leg for angiographic score and blood perfusion (assessed by laser Doppler perfusion imaging) ratios, respectively (P<0.01). Conversely, no significant changes were observed in Ang II–treated mice deficient in gene encoding for eNOS. Subhypertensive dose of Ang II enhanced angiogenesis associated with tissue ischemia through angiotensin type 1 receptor activation that involved the VEGF/eNOS-dependent pathway.
Key Words: angiogenesis • ischemia • angiotensin II • receptors, angiotensin • endothelium • nitric oxide
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