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（由适用提供）：中风的全球燃烧量很大且增长，但是我们治疗急性缺血性中风的能力受到严重限制。尽管在过去的二十年中已经做出了巨大的努力，但在临床试验中，用于治疗急性中风的神经保护剂在很大程度上失败了。溶栓和血管内治疗的成功表明，缺血性大脑的快速再灌注是预防损伤的有效手段。但是，这些疗法目前受到短时间窗口的限制，它为其提供了收益和较低的再灌注率。该项目的长期目标是了解缺血后的再灌注如何影响脑实质小动脉（PAS） - 高耐药前毛细血管前的vissels-以限制血液流向缺血区域，增加灌注防御并促进梗塞的扩张。我们的中心假设是缺血和再灌注（I/R）导致PAS过度血管收缩，从而促进了不完全的再灌注和毛细血管流动的限制。我们进一步假设，慢性高血压是中风患者的常见合并症，可通过内皮功能障碍来增加血管收缩并损害血管舒张，限制再灌注和令人担忧的中风结果。这些假设是基于我们的初步研究，这些研究表明，与经历I/R的长期血管舒张相比，PA平滑肌的钙敏感性会增强音调。PAS的收缩的钙依赖性。pas的收缩与重复的稳定相关，导致了较小的抑制作用，使您在IS/小容器中造成了不断增长的构成IS/IS的重要性。 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 sensitivity, including oxide stress activation of Rho A kinase and protein kinase C. Our preliminary studies using spontaneously hypertensive stroke prone rats （SHRSP）发现，与内皮钾通道功能受损相关的中风前后，PAS的音调增加，包括小钙激活（SKCA/IKCA）和内向整流器（KIR）钾通道，可能是血管降低以及增加的再生脂肪血液流量。这一目标2是研究高血压增强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，平滑肌钙和膜沉积与血管紧张素II在增加L型钙通道活性和内皮素-1产生中的作用之间的关系。我们还将研究高血压期间钾通道功能障碍的机理及其在血管舒张和违规受损中的作用。拟议的研究将提供有关I/R和高血压期间PA功能障碍的急需信息，这对于新的但有效的中风疗法的发展可能至关重要。