Cerebral artery Ca2+ signaling & subarachnoid hemorrhage

脑动脉 Ca2 信号传导

• 批准号: 6855926
• 负责人: GEORGE C WELLMAN
• 金额: $ 38万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6855926
• 关键词: biological signal transduction; calcium channel; calcium flux; cerebral artery; cerebral hemorrhage; confocal scanning microscopy; laboratory rabbit; muscle cells; oxyhemoglobin; pathologic process; receptor expression; subarachnoid space; vasospasm; voltage /patch clamp

DESCRIPTION (provided by applicant): Cerebral vasospasm following aneurysm rupture and subarachnoid hemorrhage (SAH) is a devastating disorder that inflicts disability and death upon thousands of individuals each year. Currently, little is known regarding the cellular mechanisms of this blood-induced cerebral artery narrowing. This proposal builds upon our work indicating that fundamental changes in Ca2+ signaling and voltage-dependent Ca2+ channel (VDCC) properties lead to enhanced constriction of cerebral arteries in an established rabbit SAH model. We have obtained exciting preliminary data indicating that SAH leads to enhanced Ca2+ entry in cerebral artery myocytes through: 1) Enhanced VDCC currents due to the emergence of R-type VDCCs (Cav 2.3), which are resistant to conventional ("L-type") calcium channel antagonists; and 2) Oxyhemoglobin, a blood component linked to vasospasm, which decreases sarcoplasmic reticulum Ca2+ release events (Ca2+ sparks) to indirectly increase VDCC activity via membrane potential depolarization. The proposed work will take an integrative approach to elucidate the impact of SAH on small diameter cerebral arteries critical to cerebral blood flow regulation by employing innovative and sophisticated electrophysiological, cell imaging and molecular biology techniques. Specific Aim 1 will test the central hypothesis that cerebral artery myocytes from control animals contain a single type of VDCCs (L-type), while cerebral artery myocytes from SAH animals contain two types of VDCCs (L-type and R-type). We propose R-type VDCCs as novel targets to treat SAIl, and that their expression indicates increased likelihood of cerebral vasospasm. Specific Aim 2 will determine the role Ca2+ sparks play in diameter regulation of cerebral arteries following SAH. We will examine whether the communication between sarcoplasmic reticulum ryanodine receptors (RyRs) and VDCCs is disrupted following SAH. The emergence of R-type VDCCs in cerebral artery myocytes following SAH provides the unique opportunity to compare the coupling strength of L-type and R-type VDCCs to RyRs in native smooth muscle. Specific Aim 3 will define the cellular events linking oxyhemoglobin to both enhanced VDCC expression and inhibition of Ca2+sparks. This study should significantly enhance current knowledge with respect to Ca2+signaling and constriction of cerebral arteries in health and disease and provide insight into possible new therapies for the treatment of cerebral vasospasm.

描述（由申请人提供）：动脉瘤破裂和蛛网膜下腔出血（SAH）后的脑血管痉挛是一种毁灭性疾病，每年造成数千人残疾和死亡。目前，关于这种血液诱导的脑动脉狭窄的细胞机制知之甚少。这一建议建立在我们的工作表明，在Ca 2+信号和电压依赖性Ca 2+通道（VDCC）的性质的根本变化，导致在一个既定的兔SAH模型的脑动脉的收缩增强。我们已经获得了令人兴奋的初步数据，表明SAH通过以下途径导致脑动脉肌细胞中Ca 2+内流增强：1）由于R型VDCC的出现而增强VDCC电流（Cav 2.3），其对常规（“L型”）钙通道拮抗剂;和2）氧合血红蛋白，一种与血管痉挛相关的血液成分，其减少肌浆网Ca 2+释放事件（Ca 2+火花）以通过膜电位去极化间接增加VDCC活性。拟议的工作将采取综合的方法来阐明蛛网膜下腔出血对小直径脑动脉的影响，通过采用创新和先进的电生理，细胞成像和分子生物学技术对脑血流调节至关重要。具体目标1将检验中心假设，即对照动物的脑动脉肌细胞含有单一类型的VDCC（L型），而SAH动物的脑动脉肌细胞含有两种类型的VDCC（L型和R型）。我们提出R型VDCCs作为治疗SAIl的新靶点，并且它们的表达表明脑血管痉挛的可能性增加。具体目标2将确定Ca 2+火花在SAH后脑动脉直径调节中的作用。我们将研究SAH后肌浆网ryanodine受体（RyRs）和VDCCs之间的通讯是否中断。SAH后脑动脉肌细胞中R型VDCCs的出现为比较L型和R型VDCCs与天然平滑肌中RyR的偶联强度提供了独特的机会。具体目标3将定义将氧合血红蛋白与增强的VDCC表达和Ca 2+火花抑制联系起来的细胞事件。这项研究应显着提高目前的知识方面的Ca 2+信号和收缩的脑动脉在健康和疾病，并提供深入了解可能的新疗法治疗脑血管痉挛。