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Abstract
Stroke remains to be a major health problem and one of the most common and undertreated disorders worldwide. With the limited treatment options, recovery is limited to the plasticity of the brain tissue and its ability to remodel after injury. Angiogenesis is a mediator of recovery and switching on angiogenesis can be achieved by the use of safe and FDA-approved medications. Experimentally, angiotensin II receptor blockers (ARBs) promoted cerebral angiogenesis with or without ischemic injury. Candesartan, a member of the ARB family, enhanced expression of vascular endothelial growth factors-A and B (VEGF-A and B) when administered after the onset of focal cerebral ischemia. In clinical trials, ARBs have demonstrated benefit in stroke prevention. However, the effect of ARB treatment in the acute phase of stroke has been complicated by its blood pressure lowering effect. In this study, we investigated the role of VEGF-A and B in mediating the benefits of ARB treatment after focal cerebral ischemia. In addition, we studied the effect of low-dose candesartan, to avoid blood pressure reduction, in combination with the anti-inflammatory and anti-apoptotic agent, minocycline, on recovery.Our findings include induction of a prolonged proangiogenic state in the brain tissue and cerebrospinal fluid after a single candesartan treatment. In addition, we demonstrated an autocrine proangiogenic and a paracrine neuroprotective effect of candesartan treatment in vitro, mediated through VEGF-A and B upregulation. The effect of candesartan treatment appeared to be a class effect of ARBs due to a similar proangiogenic response elicited by losartan treatment, another member of the ARB family. Little is known about the relatively new isoform, VEGF-B. To assess its role in mediating candesartans protective effect in acute injury, VEGF-B expression was silenced using shRNA technique. The ability of candesartan treatment to ameliorate acute injury was measured with or without VEGF-B knockdown. Lastly, we optimized ARB proangiogenic therapy by the rational sequential combination of the anti-inflammatory and MMP-inhibitory agent, minocycline. Timing of the combination treatment was optimized to avoid potential antagonistic interactions.