Targeting Parenchymal Arterioles in Acute Stroke Treatment

急性中风治疗中的靶向实质小动脉

• 批准号: 9266499
• 负责人: Marilyn J Cipolla
• 金额: $ 34.13万
• 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: 2015-07-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266499
• 关键词: Acute; Affect; Alteplase; Anastomosis - action; Angiotensin II; Animals; Architecture; Arteries; Blood capillaries; Blood flow; Brain; Calcium; Calcium-Activated Potassium Channel; Cerebrovascular Disorders; Cerebrovascular system; Chronic; Clinical; Clinical Trials; Coagulation Process; Comorbidity; Complementary therapies; Core-Binding Factor; Development; Endothelin-1; Excision; Functional disorder; Goals; Hour; Human; Hypertension; Impairment; Infarction; Injury; Ischemia; Ischemic Stroke; Knowledge; L-Type Calcium Channels; Lead; Measures; Membrane; Membrane Potentials; Muscle Tonus; Neuroprotective Agents; Outcome; Oxidative Stress; Pathway interactions; Patients; Perfusion; Peroxonitrite; Phosphotransferases; Potassium; Potassium Channel; Production; Protein Kinase C; Publishing; Rattus; Reperfusion Therapy; Resistance; Resolution; Risk Factors; Role; Site; Smooth Muscle; Stroke; Testing; Time; Tissues; Vascular blood supply; Vasoconstrictor Agents; Vasodilation; acute stroke; arteriole; base; capillary; constriction; endothelial dysfunction; functional status; improved outcome; inward rectifier potassium channel; middle cerebral artery; neuroprotection; parenchymal arterioles; prevent; public health relevance; response; restoration; rho; stroke therapy; stroke treatment; success; thrombolysis; vasoconstriction

 DESCRIPTION (provided by applicant): The global burden of stroke is substantial and growing, yet our ability to treat acute ischemic stroke is severely limited. Although considerable effort has been made in the past 2 decades, neuroprotective agents for treatment of acute stroke have largely failed in clinical trials. The success of thrombolysis and endovascular treatment demonstrates that rapid reperfusion of the ischemic brain is an effective means to prevent injury; however, these therapies are currently limited by a short time window for which it provides benefit and low rates of reperfusion. The long-term goal of this project is to understand how post-ischemic reperfusion affects brain parenchymal arterioles (PAs) - high resistance pre-capillary vessels - in ways that would limit blood flow to the ischemic region, increase perfusion deficit, and promote expansion of infarct. Our central hypothesis is that ischemia and reperfusion (I/R) cause excessive vasoconstriction of PAs that promotes incomplete reperfusion and restriction of capillary flow. We further hypothesize that chronic hypertension, a common co- morbid condition of stroke patients, increases PA vasoconstriction and impairs vasodilation through endothelial dysfunction, restricting reperfusion and worsening stroke outcome. These hypotheses are based on our preliminary studies that demonstrate that unlike middle cerebral arteries that undergo prolonged vasodilation in response to I/R, PAs have enhanced tone due to calcium sensitization of PA smooth muscle. Constriction of PAs is associated with diminished reperfusion, leading us to hypothesize that increased small vessel resistance during I/R is an important contributor to incomplete reperfusion and expansion of infarct. Thus, Aim 1 is to investigate mechanisms of PA vasoconstriction during I/R and its relationship to infarct expansion. We will determine the relationship between PA vasoconstriction and perfusion deficit during I/R, and investigate mechanisms by which I/R promote smooth muscle calcium sensitization, including oxidative stress activation of Rho A kinase and protein kinase C. Our preliminary studies using spontaneously hypertensive stroke prone rats (SHRSP) found that PAs have increased tone prior to and after stroke that is associated with impaired endothelial potassium channel function, including small- and intermediate-conductance calcium-activated (SKCa/IKCa) and inward rectifier (Kir) potassium channels that may be central to vasodilation and increasing reperfusion blood flow. Thus, Aim 2 is to investigate mechanisms by which hypertension enhances PA vasoconstriction and perfusion deficit. We will determine the relationship between PA tone, smooth muscle calcium and membrane depolarization during hypertension and the role of angiotensin II in increasing L-type calcium channel activity and endothelin-1 production. We will also investigate mechanisms of potassium channel dysfunction in PAs during hypertension and their role in impaired vasodilation and infarction. The proposed studies will provide critically needed information on PA dysfunction during I/R and hypertension that is likely to be vital in relation to development of new but effective stroke therapy.

 描述（由申请人提供）：全球中风负担巨大且不断增加，但我们治疗急性缺血性中风的能力却严重有限。尽管过去20年人们做出了相当大的努力，但用于治疗急性中风的神经保护剂在临床试验中基本上失败了。溶栓和血管内治疗的成功表明，缺血脑的快速再灌注是预防损伤的有效手段；然而，这些疗法目前受到其提供益处的时间窗口短和再灌注率低的限制。该项目的长期目标是了解缺血后再灌注如何影响脑实质小动脉（PA）（高阻前毛细血管），从而限制缺血区域的血流、增加灌注不足并促进梗塞范围扩大。我们的中心假设是缺血和再灌注 (I/R) 导致 PA 过度血管收缩，从而促进不完全再灌注和毛细血管血流限制。我们进一步假设，慢性高血压是中风患者常见的合并症，它会增加 PA 血管收缩，并通过内皮功能障碍损害血管舒张，限制再灌注并恶化中风结局。这些假设基于我们的初步研究，该研究表明，与大脑中动脉响应 I/R 而经历长时间的血管舒张不同，PA 因 PA 平滑肌的钙敏化而具有增强的张力。 PA 收缩与再灌注减少相关，因此我们推测 I/R 期间小血管阻力增加是不完全再灌注和梗塞扩大的重要原因。因此，目标 1 是研究 I/R 期间 PA 血管收缩的机制及其与梗塞扩张的关系。我们将确定 I/R 期间 PA 血管收缩和灌注不足之间的关系，并研究 I/R 促进平滑肌钙敏化的机制，包括 Rho A 激酶和蛋白激酶 C 的氧化应激激活。我们使用自发性高血压中风易感大鼠 (SHRSP) 进行的初步研究发现，PA 在中风之前和之后张力增加，这与内皮钾通道功能受损有关，包括 小电导和中电导钙激活 (SKCa/IKCa) 和内向整流 (Kir) 钾通道可能是血管舒张和增加再灌注血流量的核心。因此，目标 2 是研究高血压增强 PA 血管收缩和灌注不足的机制。我们将确定高血压期间 PA 张力、平滑肌钙和膜去极化之间的关系，以及血管紧张素 II 在增加 L 型钙通道活性和内皮素-1 产生中的作用。我们还将研究高血压期间 PA 钾通道功能障碍的机制及其在血管舒张受损和梗塞中的作用。拟议的研究将提供关于 I/R 和高血压期间 PA 功能障碍的急需信息，这对于开发新的有效中风疗法可能至关重要。