Mechanisms and Consequences of Hypertension after Stroke

描述(由申请人提供)： 我们最近发现，卒中后早期血压(BP)降低对神经血管具有强大的保护作用，这促使我们在这项竞争性更新中，继续阐明卒中后数小时内BP管理的保护作用机制。我们的长期目标是了解缺血性中风期间和之后神经血管损伤的途径，以便为中风患者设计和实施更好的治疗方法。在第一个资助期，我们确定再灌流后的降压具有神经血管保护作用，当使用血管紧张素受体阻滞剂时效果最佳。这项研究的中心假设是，即使在没有再灌流的情况下，通过早期降压实现的血管保护也能激活内源性生存蛋白，包括抗细胞凋亡和血管生成途径的那些。我们计划测试我们的中心假设，并通过以下具体目标来实现这项应用的总体目标：具体目标1：确定脑缺血和降压后的恢复程度取决于再灌注的存在和方法。我们的工作假设是，无论是否通过机械或溶栓实现再通，早期降压的神经血管保护作用都持续存在。具体目标#2：确定脑缺血后早期血压降低在多大程度上诱导内源性生存途径。我们的工作假设是，早期的血压降低会导致一种类似于“后适应”的状态，这种状态会导致持续性的血管保护，从而导致康复。这种保护依赖于抗细胞凋亡的Akt和促血管生成的血管生成因子的激活。

DESCRIPTION (provided by applicant): Our recent findings of robust neurovascular protection with early blood pressure (BP) lowering after stroke has prompted us to, in this competitive renewal, continue to elucidate mechanisms of the protective effects of BP management in the hours after stroke. Our long term goal is to understand the pathways of neurovascular injury in the brain during and after ischemic stroke in order to design and implement better treatments for stroke patients. In the first funding period, we determined that BP lowering after reperfusion is neurovascularprotective, and the best outcomes are achieved when angiotensin blockade is employed. The central hypothesis for the proposed research is that vascular protection, accomplished by early BP lowering, activates endogenous survival proteins, including those of the antiapoptosis and angiogenic pathways, even without reperfusion. We plan to test our central hypotheses and accomplish the overall objectives of this application through the following specific aims: Specific Aim #1: Determine the extent to which recovery after cerebral ischemia and BP lowering is dependent upon the presence and method of reperfusion. Our working hypothesis is that the neurovascular protective effect of early BP lowering persists whether or not reperfusion is achieved, mechanically or by thrombolysis. Specific Aim #2: Determine the extent to which early BP lowering after cerebral ischemia induces endogenous survival pathways. Our working hypothesis is that early BP lowering induces a "post conditioning"- like state that results in persistent vascular protection, leading to recovery. This protection is reliant on antiapoptotic Akt and proangiogenic VEGF activation.