Resistance Artery Adaptation in Hypertensive 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，很少有研究调查妊娠期间高血压对正常妊娠结局所必需的阻力动脉结构和功能适应的影响。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取消了正常的妊娠期抵抗动脉适应过程。使用已建立的妊娠高血压模型（一氧化氮抑制），以及几种联合治疗方案，将使我们能够区分和定义跨壁压力升高本身与NO旁分泌信号丧失对子宫和肠系膜动脉重构（Aim 1）、生物力学特性（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，这是血管重塑和顺应性的两个关键决定因素，以及对RhoA和PKC信号通路的影响，这是钙敏感性和小动脉反应性的重要决定因素。拟议的研究围绕八个工作假设进行，并在区域适应的框架内设计，因为子宫动脉和肠系膜动脉在其生理功能和对妊娠影响的适应模式方面存在很大差异。这个项目的意义在于它有可能产生新的见解，通过提高跨壁压力和/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的机制。

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.