Constrictor / Mitogen Induced Remodeling of Cerebral Arterioles

缩窄器/促细胞分裂原诱导的脑小动脉重塑

• 批准号: 7532655
• 负责人: Jay D. Humphrey
• 金额: $ 18.52万
• 依托单位: TEXAS ENGINEERING EXPERIMENT STATION
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7532655
• 关键词: Acute Brain Injuries; Arteries; Attention; Basic Science; Biomechanics; Blood Clot; Blood Vessels; Blood coagulation; Blood flow; Caliber; Cerebral Aneurysm; Cerebral Ischemia; Cerebrovascular Circulation; Cerebrovascular Spasm; Cerebrum; Clinical; Clinical Trials; Conscious; Cystamine; Data; Databases; Development; Distal; Endothelin-1; Extracellular Matrix; Foundations; Functional disorder; Future; Glutaminase; Goals; Growth; Infarction; Intracranial Aneurysm; Investigation; Messenger RNA; Mitogens; Modeling; Morbidity - disease rate; Motivation; New Zealand; Nitric Oxide; Organ Culture Techniques; Oryctolagus cuniculus; Patients; Perfusion; Plasma; Plasma Transglutaminase; Platelet-Derived Growth Factor; Play; Positioning Attribute; Process; Proteins; Public Health; Rate; Relative (related person); Research; Rho-associated kinase; Role; Rupture; Smooth Muscle; Spreading Cortical Depression; Stretching; Structure; Subarachnoid Hemorrhage; Subarachnoid Space; Surface; System; Testing; Therapeutic Intervention; Thinking; Thromboembolism; Time; Transglutaminases; Vascular remodeling; Vasocon; Vasoconstrictor Agents; Vasospasm; arteriole; base; cerebral artery; concept; crosslink; day; experience; follow-up; inhibitor/antagonist; kinase inhibitor; mathematical model; mortality; neurosurgery; novel; platelet-derived growth factor AB; pressure; research study; response

DESCRIPTION (provided by applicant): Cerebral vasospasm occurs in up to 50% of patients presenting with a subarachnoid hemorrhage (SAH), the most common cause of which is a ruptured intracranial aneurysm. This delayed process has traditionally been associated with a short-term but marked reduction in the lumen of a major cerebral artery, and thereby a reduction of distal blood flow that results in cerebral ischemia or infarction. Despite advances in neuroradiology and neurosurgery, cerebral vasospasm remains the leading cause of morbidity and mortality in patients with SAH. The primary reason for this current clinical situation is that we still do not understand well the basic mechanisms by which "vasospasm" occurs. Indeed, recent results from the CONSCIOUS-1 Clinical Trial suggest that delayed cerebral ischemia and infarction following SAH may involve many other factors in addition to the enigmatic changes in large artery caliber, structure, and function. These additional key factors may include acute brain injury, thromboembolism of small vessels, cortical spreading depression, and of particular note herein, microcirculatory dysfunction. Because of the historical focus on large vessel changes, however, little quantification is available on the relative contributions of these other factors. The goal of this R21 application, therefore, is to quantify, for the first time, biomechanical, functional, and immunohistochemical changes in cerebral arterioles that result from blood clot associated constrictors, smooth muscle mitogens, and transglutaminases that are presented to the adventitial surface (as in SAH), with particular attention to expected short-term (3-5 day) structural and functional remodeling. Toward this end, we will use our recently developed perfusion organ culture system for ~100 micron diameter arterioles to study both individually and in combination the effects of adventitially-presented endothelin-1 (ET-1, a potent vasoconstrictor and mild mitogen), platelet derived growth factor (PDGF-AB, a potent mitogen and mild vasoconstrictor), and plasma transglutaminase (pTG a potent matrix cross-linker). Of the many molecules released into the subarachnoid space due to a subarachnoid hemorrhage, these potent molecules were selected based on clinical findings in patients showing that they play key roles in vasospasm as well as recent studies on extracranial arterioles showing the ability of ET-1, PDGF, and pTG to induce marked inward remodeling within 4 days. Our study will be the first, however, on potential remodeling of cerebral arterioles and the first to test the hypothesis that diverse inhibitors have potential to block, or at least reduce, this inward remodeling by exploiting vasodilatory, anti-proliferative, and anti-crosslinking actions. Data will be collected from isolated New Zealand White Rabbit cerebral arterioles to enable comparison with the large data base on rabbit large artery remodeling due to vasospasm and will provide significantly increased data on microcirculatory dysfunction. PUBLIC HEALTH RELEVANCE Recent clinical findings and seemingly unrelated basic science findings on remodeling of arterioles collectively provide compelling motivation for a new hypothesis for the role of vascular remodeling in cerebral vasospasm, a significant cause of morbidity and mortality in patients following rupture of a cerebral aneurysm. This study will be the first to propose and test this new hypothesis as well as a potential means to block this remodeling.

描述（由申请人提供）：大脑血管痉挛发生在出现亚蛛网膜下腔出血（SAH）的患者中，最常见的原因是颅内脑动脉瘤破裂。传统上，这种延迟的过程与主要脑动脉的腔内的短期但明显减少有关，从而减少了远端血液流动，从而导致脑缺血或梗塞。尽管神经放射学和神经外科方面取得了进步，但SAH患者的发病率和死亡率的主要原因仍然是脑血管痉挛。这种当前临床情况的主要原因是，我们仍然不太了解“血管痉挛”发生的基本机制。实际上，《意识-1临床试验》的最新结果表明，除了大动脉口径，结构和功能的神秘变化之外，SAH之后延迟的脑缺血和梗塞可能还涉及许多其他因素。这些其他关键因素可能包括急性脑损伤，小血管的血栓栓塞，皮质扩散抑郁症，尤其是在此注意，微循环功能障碍。但是，由于历史上关注大容器变化，因此几乎没有关于这些其他因素的相对贡献的量化。因此，该R21应用的目的是首次量化由血块相关的约束者，平滑肌有关系和跨谷敦促的脑小动脉的生物力学，功能和免疫组织化学变化，这些变化剂和跨性别表面（如SAH）（在SAH中呈现）（如SAH），以及预期的（3-及时）。 Toward this end, we will use our recently developed perfusion organ culture system for ~100 micron diameter arterioles to study both individually and in combination the effects of adventitially-presented endothelin-1 (ET-1, a potent vasoconstrictor and mild mitogen), platelet derived growth factor (PDGF-AB, a potent mitogen and mild vasoconstrictor), and plasma transglutaminase (pTG a有效的矩阵交联）。在由于亚蛛网膜下腔出血而释放到亚蛛网膜下腔空间中的许多分子中，这些有效的分子是根据患者的临床发现选择的，表明它们在血管痉挛中起关键作用，以及最近对颅外小动脉的研究，显示了ET-1，PDGF和PTG的能力，以及在RemodeLewshard rebodeLepers中诱导的能力。但是，我们的研究将首先是对脑动脉的潜在重塑，并且第一个检验了多种抑制剂有可能阻止或至少减少这种向内重塑的假说，通过利用血管舒张，抗增殖性和抗链接作用。数据将从新西兰孤立的白兔脑小动脉中收集，以便与由于血管痉挛引起的兔大动脉重塑的大数据库进行比较，并将为微循环功能障碍的数据显着增加。公共卫生相关性最近的临床发现以及有关小动脉重塑的看似无关的基础科学发现，为脑血管痉挛中血管重塑的作用提供了令人信服的动机，这是脑血管痉挛中发病率和死亡率的重要原因，这是脑部脑部破裂后发病率和死亡率的重要原因。这项研究将是第一个提出和检验这一新假设的研究，以及阻止这种重塑的潜在手段。