Targeting pial collaterals for acute stroke treatment

脑软膜侧支循环是急性缺血性卒中结果的最重要预测因子。 闭塞时影像学上侧支状况良好的患者可挽救组织更多，体积更小 缺血性核心，以及大血管闭塞（LVO）后更好的神经学结果。相比之下，患者 即使实现再通，不良的抵押品也会带来更糟糕的结果。 Pial 抵押品是一个网络 软脑膜吻合术（LMA），维持半暗带（血液受限的区域）的灌注 如果发生再灌注，供应可能可以挽救。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流的治疗方法，特别是在以下情况下 侧支循环灌注不良，如慢性高血压。我们之前的研究发现 LMA 自发性高血压大鼠（SHR）血管高度收缩，对压力的反应强烈 在用于模拟 LVO 的大脑中动脉闭塞 (MCAO) 过程中，肌源性收缩在体内持续存在。 这与血压正常的 Wistar 大鼠的 LMA 形成鲜明对比，后者的血管舒张程度更高，基础张力很小。 我们的中心假设是高血压促进 LMA 的血管收缩并损害血流介导的血管 LVO 期间限制半暗带灌注的扩张。我们的初步和已发布的数据支持以下作用： 血管紧张素 II (Ang II) 和纤溶酶原激活抑制剂-1 (PAI-1) 作为高血压的潜在机制 通过直接抑制内皮一氧化氮合酶（eNOS）诱导 LMA 血管收缩。目标1 将确定 Ang II、PAI-1 和瞬时受体电位 vanilliod 4 (TRPV4) 的作用，剪切应力- 反应性离子通道，介导正常血压和高血压雄性和雌性大鼠的侧支血流。我们 还将研究慢性高血压期间侧支血流受损和 LMA 功能障碍的机制。 我们的初步数据还发现，诱发高血压——急剧升高血压以增强血压 LVO 期间的侧支灌注 – 血压正常的大鼠侧支血流增加，这可能在 SHR 中受到限制 由于 LMA 血管收缩。然而，PAI-1 抑制剂的血管舒张增加了 SHR 的侧支血流， 导致我们假设在闭塞期间扩张 LMA 的治疗将改善侧支血流并延长 SHR 中再灌注的时间窗口。因此目标 2 是确定诱发高血压的功效 以及血管舒张作为 LVO 结果的并行治疗。我们将使用获得的机械信息 目标 1 指导目标 2 并测试半影灌注、氧合和长期治疗的临床相关治疗 LVO 的长期结果。该项目的结果将为pial的功能提供有价值的信息 对于中风治疗和 LVO 结局至关重要的络脉。

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.