Mechanisms of High Flow Induced Vasculopathy

高流量诱发血管病变的机制

• 批准号: 6718424
• 负责人: ELIZABETH R JACOBS
• 金额: $ 32.66万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6718424
• 关键词: calcium channel; cardiovascular injury; eicosanoids; nitric oxide synthase; pathologic process; pulmonary artery; second messengers; shear stress; swine; vascular endothelium; vascular resistance; vascular smooth muscle; vasomotion; voltage gated channel

DESCRIPTION (provided by applicant): Increased flow induces a series of vascular responses, the earliest of which are prodilatory and largely endothelial mediated, followed by the development of myogenic tone (which serves to return blood flow towards baseline) and enhanced reactivity to agonists. The mechanisms, which underlie this heightened response to contractile agents, are incompletely understood, but likely involve ion channel-mediated transduction of signals in endothelial and vascular smooth muscle cells. We have developed a model of high flow to isolated lung lobes of young pigs (created by an aorto-pulmonary anastomosis) which results in neointimal proliferation characteristic of clinical pulmonary hypertension and early enhanced reactivity which reactivity appears to be endothelial and L-type calcium channel dependent. Our preliminary data suggest that sustained flow results in increased expression of voltage-gated calcium channels and dysfunctions in NOS which may contribute to enhanced reactivity of shunted arteries. We hypothesize that acutely enhanced synthesis of endothelial-derived EETs increases opening of L-type calcium and decreases the opening of calcium activated K channels in subjacent PAVSMs following increased flow. The specific aims of the grant are threefold: (i) We will identify the contribution of the endothelial second messenger signaling pathways including PLC, EETs, NOS and Ca(L) and KCa ion channels in vascular smooth muscle cells to the tone and reactivity of PAs exposed to high or baseline flows. (2) We will characterize flow-induced changes in expression of eNOS levels in PAs as well as expression of Ca(L) and KCa type ion channels in pulmonary artery vascular smooth muscle cells. (3) We will examine flow-induced changes in activity of endothelial second messenger signaling cascades PLC, EETs, NOS, gating of Ca(L) and KCa channels in PAVSM, and effect of EETs on [Ca2+]i in PAVSMCs of shunted versus non-shunted pulmonary arteries. These studies should yield valuable information about cellular mechanisms which underlie high flow induced vasculopathy, which conditions complicate a number of clinically important conditions such as repair of congenital heart defects, pneumonectomies, and others.

描述（由申请人提供）：血流增加引起一系列血管反应，其中最早的是前伸性且主要是内皮介导的，随后是肌源张力的发展（其用于使血流返回基线）和对激动剂的反应性增强。这种对收缩剂的强烈反应的机制尚不完全清楚，但可能涉及内皮和血管平滑肌细胞中离子通道介导的信号转导。我们开发了一种高流量流向幼猪离体肺叶的模型（通过主动脉肺吻合术创建），该模型导致临床肺动脉高压的新内膜增殖特征和早期反应性增强，该反应性似乎是内皮和L型钙通道依赖。我们的初步数据表明，持续血流会导致电压门控钙通道表达增加和 NOS 功能障碍，这可能有助于增强分流动脉的反应性。我们假设内皮源性 EET 合成的急剧增强会增加 L 型钙的开放，并在流量增加后减少下方 PAVSM 中钙激活 K 通道的开放。该资助的具体目标有三个：(i) 我们将确定内皮第二信使信号通路（包括 PLC、EET、NOS 以及血管平滑肌细胞中的 Ca(L) 和 KCa 离子通道）对血管平滑肌细胞张力和反应性的贡献。 PA 暴露于高流量或基线流量。 (2) 我们将表征流动诱导的 PA 中 eNOS 水平表达的变化以及肺动脉血管平滑肌细胞中 Ca(L) 和 KCa 型离子通道的表达。 (3) 我们将检查血流诱导的内皮第二信使信号级联 PLC、EET、NOS 活性的变化，PAVSM 中 Ca(L) 和 KCa 通道的门控，以及 EET 对分流与分流组 PAVSMC 中 [Ca2+]i 的影响非分流肺动脉。这些研究应该会产生关于高流量诱发的血管病变的细胞机制的有价值的信息，这种情况使许多临床上重要的病症复杂化，例如先天性心脏缺陷的修复、肺切除术等。