Targeting pial collaterals for acute stroke treatment

针对急性中风治疗的软脑膜侧支循环

• 批准号: 10412122
• 负责人: Marilyn J Cipolla
• 金额: $ 48.04万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10412122
• 关键词: Acute; Anastomosis - action; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Behavioral; Blood Pressure; Blood flow; Brain; Cell Death; Cerebrum; Chronic; Clinical; Collateral Circulation; Data; Distal; Endothelium; Evolution; Female; Functional disorder; Goals; Hydralazine; Hypertension; Image; Impairment; Implanted Electrodes; In Vitro; Inbred SHR Rats; Infarction; Ion Channel; Ischemia; Ischemic Stroke; Knowledge; Legal patent; Measures; Mediating; Middle Cerebral Artery Occlusion; NOS3 gene; Neurological outcome; Neuroprotective Agents; Nitric Oxide Synthase; Outcome; Pathway interactions; Patients; Perfusion; Plasminogen; Plasminogen Activator Inhibitor 1; Publishing; Rattus; Receptor, Angiotensin, Type 1; Reperfusion Therapy; Role; Serine Protease; Stroke; Telemetry; Testing; Therapeutic; Time; Tissues; Treatment outcome; Vanilloid; Vascular Diseases; Vascular blood supply; Vasodilation; Wistar Rats; acute stroke; arteriole; blood pressure elevation; blood pressure reduction; clinically relevant; comorbidity; constriction; effective therapy; endothelial dysfunction; experimental study; functional status; hypertensive; improved; improved outcome; in vivo; inhibitor; male; normotensive; outcome prediction; pressure; prevent; receptor; response; sex; shear stress; stroke outcome; stroke patient; stroke therapy; therapeutic target; thrombolysis; vasoconstriction; wireless

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.

脑部侧支循环是急性缺血性中风结果最重要的预测指标。 在遮挡时成像良好的附带状态的患者具有更多可挽救的组织，较小 缺血性核心，并在大血管闭塞后更好的神经系统结局（LVO）。相反，患者 即使实现了重新加续化，较差的抵押品的结果也会更糟。皮拉抵押品是一个网络 瘦脑膜吻合术（LMA）保持灌注对半阴茎，该区域受约束的血液 如果发生再灌注，则可能可以挽救的供应。我们的总体目标是了解LMA的功能 并开发在LVO期间维持或增加半流量的治疗方法，尤其是在 副灌注不良，例如慢性高血压。我们以前的研究发现LMA来自 赞助的高血压大鼠（SHR）高度血管收缩，并以强大的响应对压力做出反应 在脑动脉闭塞期间（MCAO）持续存在的肌源性收缩（MCAO）用于模仿LVO。 这与正常的Wistar大鼠的LMA相反，后者更加血管延伸，基础音调几乎没有。 我们的中心假设是高血压促进LMA的血管收缩并损害流量介导的 在LVO期间，扩张将灌注限制为半月。我们的初步和已发布的数据支持 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）引起的LMAS诱导血管收缩。目标1 将确定ANG II，PAI-1和瞬态受体电位Vanilliod 4（TRPV4）的作用，剪切应力 - 反应性离子通道，在介导正常和高血压的男性和雌性大鼠中介导侧支流中。我们 还将研究慢性高血压期间侧支流和LMA功能障碍受损的机制。 我们的初步数据还发现，诱导的高血压 - 急性增加血压以增强 LVO期间的侧支灌注 - 正常性大鼠的侧支流量增加的SHR，可能 由于血管收缩的LMA。然而，用PAI-1抑制剂的血管舒张增加了SHR中的侧支流动， 导致我们假设在闭塞过程中扩张LMA的治疗方法将改善附带流量并延伸 SHR中再灌注的时间窗口。因此，目标2是确定诱导高血压的效率 和血管舒张作为LVO结果的抵押疗法。我们将使用获得的机械信息 在AIM 1下指导AIM 2并测试有关半体灌注，氧合和长长的临床相关治疗 LVO的术语结果。该项目的结果将提供有关PIAL功能的宝贵信息 LVO的中风治疗和结果的核心。