Tamarat Radia, Silvestre Jean-Sébastien, Kubis Nathalie, Benessiano Joelle, Duriez Micheline, deGasparo Marc, Henrion Daniel, Levy Bernard I
INSERM U541, Hôpital Lariboisière, IFR Circulation-Paris 7, Université Paris 7-Denis Diderot, Paris, France.
Hypertension. 2002 Mar 1;39(3):830-5. doi: 10.1161/hy0302.104671.
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 microg 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.
我们评估了血管紧张素（Ang）II在缺血诱导的血管生成中的作用，并分析了参与这种作用的分子途径。通过对对照组、缬沙坦治疗组（血管紧张素II 1型受体拮抗剂，每天20mg/kg）、Ang II治疗组（每分钟5ng/kg）以及Ang II和缬沙坦联合治疗组的大鼠进行单侧股动脉闭塞来制造缺血模型。28天后，通过微血管造影和测量后肢毛细血管密度来评估血管生成情况。与对照组相比，Ang II治疗组大鼠血管造影评分和毛细血管数量的缺血/非缺血腿比值分别增加了2.6倍和2倍（P<0.01）。通过蛋白质印迹法评估发现，这与缺血腿中血管内皮生长因子（VEGF；1.6倍）和内皮型一氧化氮合酶（eNOS；1.8倍）蛋白含量的增加有关。在Ang II治疗组大鼠中，阻断血管紧张素1型受体并给予VEGF中和抗体（腹腔注射2.5μg，每周两次）可完全阻止Ang II的血管生成作用。然后，通过使用编码eNOS的基因缺陷小鼠强调了eNOS的关键作用。在野生型小鼠中，Ang II（每分钟0.3mg/kg）治疗使血管造影评分的缺血/非缺血腿比值和血液灌注（通过激光多普勒灌注成像评估）比值分别增加了1.7倍和1.6倍（P<0.01）。相反，在编码eNOS的基因缺陷的Ang II治疗小鼠中未观察到显著变化。亚高血压剂量的Ang II通过血管紧张素1型受体激活增强了与组织缺血相关的血管生成，该激活涉及VEGF/eNOS依赖性途径。
