Shanab Ahmed Y, Elshaer Sally L, El-Azab Mona F, Soliman Sahar, Sabbineni Harika, Matragoon Suraporn, Fagan Susan C, El-Remessy Azza B
Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, 30912, USA.
Angiogenesis. 2015 Apr;18(2):137-50. doi: 10.1007/s10456-014-9451-4. Epub 2014 Nov 25.
Ischemic diseases such as stroke and proliferative retinopathy are characterized by hypoxia-driven release of angiogenic factors such as vascular endothelial growth factor (VEGF). However, revascularization of the ischemic areas is inadequate, resulting in impaired neuro-vascular function. We aim to examine the vascular protective effects of candesartan, an angiotensin receptor blocker, in an ischemic retinopathy mouse model. Vascular density, number of tip cells, and perfusions of capillaries were assessed. Activation of Muller glial cells and levels of peroxynitrite, VEGF, VEGFR2, inducible nitric oxide synthase, hemeoxygenase-1 (HO-1) were assessed. Proangiogenic effects of candesartan were examined in human endothelial cells (EC) that were cultured in normoxia or hypoxia and transduced with siRNA against HO-1. Candesartan (1 mg/kg) and (10 mg/kg) decreased hypoxia-induced neovascularization by 67 and 70%, respectively. Candesartan (10 mg/kg) significantly stimulated the number of tip cells and physiological revascularization of the central retina (45%) compared with untreated pups. The effects of candesartan coincided with reduction of hypoxia-induced Muller glial activation, iNOS expression and restoration of HO-1 expression with no significant change in VEGF levels. In vitro, silencing HO-1 expression blunted the ability of candesartan to induce VEGF expression under normoxia and VEGFR2 activation and angiogenic response under both normoxia and hypoxia. These findings suggest that candesartan improved reparative angiogenesis and hence prevented pathological angiogenesis by modulating HO-1 and iNOS levels in ischemic retinopathy. HO-1 is required for VEGFR2 activation and proangiogenic action of candesartan in EC. Candesartan, an FDA-approved drug, could be repurposed as a potential therapeutic agent for the treatment of ischemic diseases.
诸如中风和增殖性视网膜病变等缺血性疾病的特征是缺氧驱动血管生成因子如血管内皮生长因子（VEGF）的释放。然而，缺血区域的血管再生不足，导致神经血管功能受损。我们旨在研究血管紧张素受体阻滞剂坎地沙坦在缺血性视网膜病变小鼠模型中的血管保护作用。评估了血管密度、尖端细胞数量和毛细血管灌注情况。评估了穆勒神经胶质细胞的激活以及过氧亚硝酸盐、VEGF、VEGFR2、诱导型一氧化氮合酶、血红素加氧酶-1（HO-1）的水平。在常氧或缺氧条件下培养并用针对HO-1的小干扰RNA转导的人内皮细胞（EC）中检测了坎地沙坦的促血管生成作用。坎地沙坦（1毫克/千克）和（10毫克/千克）分别使缺氧诱导的新生血管形成减少了67%和70%。与未治疗的幼崽相比，坎地沙坦（10毫克/千克）显著刺激了尖端细胞数量以及视网膜中央的生理性血管再生（45%）。坎地沙坦的作用与缺氧诱导的穆勒神经胶质细胞激活减少、诱导型一氧化氮合酶表达降低以及HO-1表达恢复同时出现，而VEGF水平无显著变化。在体外，沉默HO-1表达削弱了坎地沙坦在常氧条件下诱导VEGF表达的能力以及在常氧和缺氧条件下激活VEGFR2和血管生成反应的能力。这些发现表明，坎地沙坦通过调节缺血性视网膜病变中的HO-1和诱导型一氧化氮合酶水平改善了修复性血管生成，从而预防了病理性血管生成。HO-1是VEGFR2激活以及坎地沙坦在EC中的促血管生成作用所必需的。坎地沙坦是一种经美国食品药品监督管理局批准的药物，可重新用作治疗缺血性疾病的潜在治疗剂。
