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 相比之下，大血管闭塞（LVO）后的患者具有更好的神经功能。 即使实现再通，不良的抵押品也会产生更差的结果。 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，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，例如慢性高血压，我们之前的研究发现，LMAs 来自于慢性高血压。 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 我们的初步和已发表的数据支持 LVO 期间限制半暗带灌注的扩张。 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。 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。 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 然而，由于 LMA 血管收缩，PAI-1 抑制剂的血管舒张增加了 SHR 的侧支血流。 使我们认识到，在闭塞期间扩张 LMA 的治疗将改善侧支循环并延长 因此，目标 2 是确定诱导高血压的功效。 和血管舒张作为 LVO 结果的辅助治疗我们将使用获得的机制信息。 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 的长期成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。