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Resistance Artery Adaptation in Hypertensive Pregnancy

妊娠期高血压的阻力动脉适应

基本信息

批准号：
7590316
负责人：
George J Osol
金额：
$ 33.21万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2010-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7590316
关键词：
Accounting Affect Age Animals Aorta Area Arteries Biological Preservation Biomechanics Blood Circulation Blood Pressure Blood Vessels Calcium Caliber Cell physiology Cells Cellularity Cessation of life Chronic Clinical Cyclic GMP Data Development Effectiveness Elastin Extracellular Matrix Failure Fetal Growth Retardation Fetal Weight Gelatinase A Gelatinase B Growth Hormonal Human Hydralazine Hypertension Hypertension induced by pregnancy Kidney Lead Length Link Matrix Metalloproteinases Mechanics Mesenteric Arteries Mesentery Modeling Molecular Morbidity - disease rate NG-Nitroarginine Methyl Ester Neonatal Mortality Nitric Oxide Nitric Oxide Pathway Paracrine Communication Pathway interactions Pattern Perfusion Peripheral Resistance Phenotype Phenylephrine Physiological Pre-Eclampsia Pregnancy Pregnancy Outcome Property Protein Isoforms Proteins Proteinuria Publishing Rattus Regulation Research Research Personnel Resistance Resistance Process Rodent Model S-Phase Fraction Signal Pathway Signal Transduction Smooth Muscle Splanchnic Circulation Stimulus Structure Thick Thrombocytopenia Treatment Protocols Vascular remodeling Vasoconstrictor Agents Vasodilation Vasodilator Agents Viagra Woman Work base design drinking water fetal in vivo insight interest mortality muscular structure normotensive phosphodiesterase V phosphoric diester hydrolase pregnant pressure prevent programs protein activation regional difference response rho sildenafil

项目摘要

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(申请人提供)：妊娠期高血压是全球孕产妇发病率和死亡率的主要原因，占与妊娠有关的死亡的10%。尽管外周阻力升高是高血压的标志，但令人惊讶的是，很少有研究研究妊娠期高血压对阻力动脉结构和功能适应的影响，这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废除阻力动脉妊娠适应的正常过程。使用已建立的妊娠期高血压模型(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和NO旁分泌信号丢失对子宫和肠系膜动脉重构(目标1)、生物力学特性(目标2)、收缩能力(目标3)和VSM表型表达(目标4)的妊娠变化的影响。从机制的角度来看，我们尤其感兴趣的是了解高血压/NO丢失对基质金属蛋白酶活性和弹性蛋白含量的影响，这两个因素是血管重塑和顺应性的关键决定因素，以及对RhoA和PKC信号通路的影响，这两个信号通路是钙敏感性和小动脉反应性的重要决定因素。由于子宫动脉和肠系膜动脉在生理功能和对妊娠影响的适应模式上有很大的不同，拟议的研究围绕八个工作假设进行设计，并在区域适应的框架内进行设计。这个项目的意义在于，它有可能对跨壁压升高和/或一氧化氮信号减少影响怀孕期间血管平滑肌结构、功能和表型适应的机制产生新的见解。