Resistance Artery Adaptation in Hypertensive Pregnancy

妊娠期高血压的阻力动脉适应

• 批准号: 6919759
• 负责人: George J Osol
• 金额: $ 34.2万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6919759
• 关键词: arterioles; biological signal transduction; calcium ion; capillary bed; captopril; elastin; hydralazine; laboratory rat; mesenteric artery; metalloendopeptidases; muscle function; nitric oxide; paracrine; pregnancy circulation; pregnancy circulation disorder; pregnancy disorder chemotherapy; pregnancy toxemia /hypertension; protein kinase C; uterus; vascular resistance; vascular smooth muscle

DESCRIPTION (provided by applicant): Hypertension during pregnancy is a leading cause of maternal morbidity and mortality worldwide, accounting for up to 10% of pregnancy-related deaths. Although elevated peripheral resistance is the hallmark of hypertension, surprisingly few studies have examined the effects of hypertension during pregnancy on resistance artery structural and functional adaptation that is essential for normal pregnancy outcome. In this project, the unifying hypothesis is that maternal hypertension abrogates the normal process of resistance artery gestational adaptation through specific and identifiable cellular mechanisms that govern vessel reactivity and structure. The use of an established model of gestational hypertension (nitric oxide inhibition), along with several co-treatment protocols, will allow us to distinguish and define the consequences of elevated transmural pressure per se vs. loss of NO paracrine signaling on gestational changes in uterine and mesenteric artery remodeling (Aim 1), biomechanical properties (Aim 2), contractility (Aim 3) and VSM phenotypic expression (Aim 4). From a mechanistic standpoint, we are particularly interested in understanding the impact of hypertension/NO loss on matrix metalloproteinase activity and elastin content, two critical determinants of vascular remodeling and compliance, and on the RhoA and PKC signalling pathways that are important determinants of calcium sensitivity and small artery reactivity. The proposed studies are structured around eight working hypotheses and are designed within the framework of regional adaptation, as uterine and mesenteric arteries differ substantially in their physiological function, and in their patterns of adaptation to gestational influences. The significance of this project lies in its potential for generating new insights into the mechanisms by which elevated transmural pressure and/or reduced nitric oxide signaling influences vascular smooth muscle structure, function and phenotypic adaptation during pregnancy.

描述（由申请人提供）：怀孕期间的高血压是全球孕产妇发病率和死亡率的主要原因，占与怀孕有关的死亡的10％。尽管外围耐药性升高是高血压的标志，但令人惊讶的是，很少有研究检查怀孕期间高血压对耐药性动脉结构和功能适应的影响，这对于正常妊娠结局至关重要。在这个项目中，统一的假设是，母体高血压通过控制血管反应性和结构的特定和可识别的细胞机制来消除抗药性动脉妊娠适应的正常过程。使用已建立的妊娠高血压模型（一氧化氮抑制），以及几种共同处理方案，将使我们能够区分和定义跨甲壳压力上升高的后果本质上，无旁分泌信号传导与子宫和膜型动脉重塑（AIM 1），AIM机械物质（AIM 2），目标（目标）（目标）（目标）（目标）（目标）（目标2） （目标4）。从机械的角度来看，我们特别有兴趣了解高血压/无损失对基质金属蛋白酶活性和弹性蛋白含量的影响，两个关键的血管重塑和依从性的关键决定因素，以及RhoA和PKC信号传导途径，这些信号途径是钙敏感性和小动脉反应性的重要决定因素。拟议的研究是在八个工作假设围绕的，并在区域适应的框架内设计，因为子宫和肠系膜动脉在其生理功能以及适应妊娠影响的模式下有很大差异。该项目的重要性在于它的潜力是对升高的透壁压力和/或一氧化氮信号升高的机制产生新的见解，从而影响妊娠期间血管平滑肌结构，功能和表型适应。