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）：妊娠期高血压是全球孕产妇发病和死亡的主要原因，占妊娠相关死亡的10%。虽然外周阻力升高是高血压的标志，但令人惊讶的是，很少有研究探讨妊娠期高血压对阻力动脉结构和功能适应的影响，而阻力动脉结构和功能适应对正常妊娠结局至关重要。在这个项目中，统一的假设是，母体高血压废除阻力动脉妊娠适应的正常过程，通过特定的和可识别的细胞机制，管理血管的反应性和结构。妊娠期高血压模型的应用（一氧化氮抑制），沿着几种联合治疗方案，将使我们能够区分和定义跨壁压升高本身与NO旁分泌信号丢失对子宫和肠系膜动脉重塑（Aim 1）、生物力学性质（Aim 2）、收缩性（Aim 3）和VSM表型表达（Aim 4）的妊娠变化的后果。从机制的角度来看，我们特别感兴趣的是了解高血压/NO损失对基质金属蛋白酶活性和弹性蛋白含量的影响，这两个关键的决定因素血管重塑和顺应性，以及对RhoA和PKC信号通路的钙敏感性和小动脉反应性的重要决定因素。拟议的研究是围绕八个工作假设，并在区域适应的框架内设计，子宫和肠系膜动脉在其生理功能和妊娠影响的适应模式方面存在很大差异。该项目的意义在于其潜在的产生新的见解的机制，提高跨壁压和/或减少一氧化氮信号影响血管平滑肌结构，功能和表型适应在怀孕期间。