Targeting pial collaterals for acute stroke treatment

脑软脑膜侧支循环是预测急性缺血性卒中预后的最重要指标。 闭塞时影像显示侧支状态良好的患者有更多可挽救的组织，较小 大血管闭塞(LVO)后的缺血核心和更好的神经预后。相比之下，患有 即使实现了再通，不良抵押贷款的结果也会更差。软脑膜经络是一种 软脑膜吻合术(LMA)，维持对半影区的灌流，半影区是一个血液受限的区域 如果再灌流发生，潜在可挽救的供应。我们的总体目标是了解LMA的功能 并开发在LVO期间维持或增加半暗带血流的治疗方法，特别是在以下情况下 侧支循环血流灌注差，如慢性高血压。我们之前的研究发现，来自 自发性高血压大鼠(SHR)血管高度收缩，对压力反应强烈 在大脑中动脉闭塞(MCAO)期间，体内持续存在的肌源性收缩用于模拟LVO。 这与血压正常的Wistar大鼠的LMA形成了鲜明对比，后者的血管扩张程度更高，基础张力很小。 我们的中心假设是，高血压促进LMA的血管收缩，损害血流介导的 在左心室关闭时，扩张限制了对半影区的血流。我们的初步和公布的数据支持一个角色 血管紧张素II(Ang II)和纤溶酶原激活抑制物-1(PAI-1)是高血压的潜在机制 通过直接抑制内皮型一氧化氮合酶(ENOS)诱导LMA的血管收缩。目标1 将决定血管紧张素II、纤溶酶原激活物-1和瞬时受体电位香草素4(TRPV4)的作用，切应力- 反应离子通道，介导正常血压和高血压雌雄大鼠的侧支循环。我们 还将调查慢性高血压期间侧支循环受损和LMA功能障碍的机制。 我们的初步数据还发现，诱发性高血压--急性升高的血压增强 LVO期间的侧支血流--正常血压大鼠侧支血流增加，这在自发性高血压大鼠中可能是有限的 是由于血管收缩的LMA所致。然而，PAI-1抑制剂的血管扩张增加了SHR的侧支循环血流量， 这导致我们假设，在闭塞期间扩张LMA的治疗将改善侧支循环并延长 自发性高血压大鼠再灌注的时间窗。因此，目标2是确定诱发性高血压的疗效。 血管扩张作为侧支治疗对LVO预后的影响。我们将使用获得的机械性信息 在目标1下，指导目标2，并测试临床上相关的治疗方法，包括半影区的血流灌注、氧合和长时间 来自LVO的长期结果。该项目的结果将提供关于pial功能的有价值的信息。 对卒中治疗和左心室阻塞预后至关重要的络脉。

The cerebral pial collateral circulation is the most important predictor of outcome from acute ischemic stroke. Patients with good collateral status on imaging at the time of occlusion have more salvageable tissue, smaller ischemic cores, and better neurological outcome after large vessel occlusion (LVO). In contrast, patients with poor collaterals have worse outcome even if recanalization is achieved. Pial collaterals are a network of leptomeningeal anastomoses (LMAs) that maintain perfusion to the penumbra, a region with constrained blood supply that is potentially salvageable if reperfusion occurs. Our overall goal is to understand the function of LMAs and develop treatments that sustain or increase penumbral flow during LVO, especially under conditions that have poor collateral perfusion such as chronic hypertension. Our previous study found that LMAs from spontaneously hypertensive rats (SHR) were highly vasoconstricted and responded to pressure with robust myogenic constriction that persisted in vivo during middle cerebral artery occlusion (MCAO) used to mimic LVO. This was in contrast to LMAs from normotensive Wistar rats that were more vasodilated and had little basal tone. Our central hypothesis is that hypertension promotes vasoconstriction of LMAs and impairs flow-mediated dilation that limits perfusion to the penumbra during LVO. Our preliminary and published data support a role for angiotensin II (Ang II) and plasminogen activated inhibitor-1 (PAI-1) as underlying mechanisms of hypertension- induced vasoconstriction of LMAs through direct inhibition of endothelial nitric oxide synthase (eNOS). Aim 1 will determine the role of Ang II, PAI-1 and the transient receptor potential vanilliod 4 (TRPV4), a shear stress- responsive ion channel, in mediating collateral flow in normotensive and hypertensive male and female rats. We will also investigate mechanisms of impaired collateral flow and LMA dysfunction during chronic hypertension. Our preliminary data also found that induced hypertension – acutely increasing blood pressure to enhance collateral perfusion during LVO – increased collateral flow in normotensive rats that was limited in SHR, likely due to vasoconstricted LMAs. However, vasodilation with a PAI-1 inhibitor increased collateral flow in SHR, leading us to hypothesize that treatment to dilate LMAs during occlusion will improve collateral flow and extend the time window for reperfusion in SHR. Therefore Aim 2 is to determine the efficacy of induced hypertension and vasodilation as collateral therapeutics on outcome from LVO. We will use the mechanistic information gained under Aim 1 to guide Aim 2 and test clinically relevant treatments on penumbral perfusion, oxygenation and long- term outcome from LVO. The results of this project will provide valuable information on the function of pial collaterals that are central to stroke treatment and outcome from LVO.