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: 10309056
• 负责人: Marilyn J Cipolla
• 金额: $ 45.58万
• 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/10309056
• 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; Wireless Technology; Wistar Rats; acute stroke; arteriole; blood pressure reduction; clinically relevant; comorbidity; constriction; effective therapy; endothelial dysfunction; experimental study; functional status; improved; improved outcome; in vivo; inhibitor/antagonist; male; normotensive; outcome prediction; pressure; prevent; receptor; response; sex; shear stress; stroke outcome; stroke patient; stroke therapy; therapeutic target; thrombolysis; vasoconstriction

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预后的最重要预测因素。 闭塞时影像学显示侧支状态良好的患者有更多的可挽救组织， 大血管闭塞（LVO）后，缺血核心和更好的神经功能结局。相反，患者 即使实现再通，不良侧支也具有更差的结果。软脑膜侧支是一个网络， 软脑膜炎（LMA），维持对半暗带（血液受限区域）的灌注 如果再灌注发生，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期间维持或增加半影血流的治疗方法，特别是在 侧支灌注差，如慢性高血压。我们之前的研究发现， 自发性高血压大鼠（SHR）血管高度收缩，对压力的反应具有鲁棒性。 在大脑中动脉闭塞（MCAO）过程中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形成对比，后者血管舒张更多，基础张力很小。 我们的中心假设是，高血压促进血管收缩的LMAs和损害流量介导的 LVO期间限制半暗带灌注的扩张。我们的初步和公布的数据支持的作用， 血管紧张素II（Ang II）和纤溶酶原激活抑制剂-1（派-1）作为高血压的潜在机制- 通过直接抑制内皮型一氧化氮合酶（eNOS）诱导LMA的血管收缩。要求1 将决定血管紧张素II，派-1和瞬时受体电位香草醛4（TRPV 4）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受损的侧支血流和LMA功能障碍的机制。 我们的初步数据还发现，诱发性高血压-急性增加血压，以提高 LVO期间的侧支灌注-在血压正常的大鼠中增加侧支血流，这在SHR中是有限的，可能 因为血管收缩性脑脊髓膜炎然而，派-1抑制剂的血管舒张增加了SHR的侧支血流， 这使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再灌注时间窗。因此，目的2是确定诱导性高血压的疗效 和血管扩张作为LVO结局的辅助治疗。我们将利用获得的机械信息 根据目标1，指导目标2，并测试半暗带灌注、氧合和长时间的临床相关治疗。 LVO的远期结局。本研究结果将为软脑膜的功能研究提供有价值的信息 对卒中治疗和LVO结局至关重要的侧枝循环。