Steroid Hormones and Uterine Vascular Adaptation to Pregnancy

描述(由申请者提供)：该项目的长期目标是了解怀孕期间子宫血流调节的潜在机制。以前的体内研究表明，雌激素和孕酮在调节妊娠期间的子宫血流中起着重要作用。除了对内皮细胞一氧化氮合成/释放的影响外，类固醇激素对子宫动脉收缩适应妊娠的直接影响和机制尚不清楚。最近，我们已经证明，PKC和ERK1/2相互作用并调节阻力大小的子宫动脉的压力诱导的肌源性张力，这种张力在怀孕动物中显著减弱。压力依赖性肌性收缩是调节基础血管张力的重要生理机制，也是血流调节的主要因素。我们的初步数据显示，生理相关浓度的雌激素和孕酮具有直接的基因组效应，上调ERK1/2并抑制PKC介导的子宫动脉肌源性收缩。这些研究将集中在机制上，并检验主要假设，即类固醇激素不同地调节ERK1/2和PKC信号通路，导致怀孕期间子宫动脉肌动蛋白聚合和肌源性张力下降。为了验证这一假说，我们制定了3个特定的目标，它们将确定：1)雌激素/孕酮上调子宫动脉ERK1/2基因的表达并抑制PKC活性；2)ERK1/2和PKC对妊娠期间子宫动脉肌动蛋白聚合和肌源性血管张力的不同调节；3)雌激素和孕酮通过调节子宫动脉ERK/PKC通路抑制肌动蛋白聚合和抑制血管张力。这项研究将在体外组织培养模型系统中对未怀孕和怀孕的绵羊子宫动脉进行，并将确定类固醇激素对子宫动脉ERK1/2和PKC同工酶的基因表达模式和活性、肌动蛋白聚合以及压力诱导的肌源性收缩的直接影响。这些结果将为类固醇激素在妊娠期子宫胎盘循环适应中的机制提供令人兴奋的新见解，具有明显的临床意义，因为子宫循环对妊娠的不良适应与胎儿发育异常和母体心血管疾病有关。 公共卫生相关性：在人类怀孕期间，子宫血流量显著增加，确保了胎儿的正常发育。除了子宫血管的生长和重塑外，由于子宫动脉的松弛和收缩减少，子宫血管阻力也显著降低。子宫动脉收缩适应妊娠的机制是复杂的，目前还不完全清楚。这些研究将探讨类固醇激素在妊娠期子宫循环适应中的分子机制，并将有助于了解与不良适应和异常妊娠相关的临床问题，这些问题会导致许多胎儿发育异常，包括宫内生长受限，以及包括妊娠期高血压在内的母体心血管疾病。此外，这些研究将为了解心血管疾病的胎儿起源提供非常有用的信息，这是现代医学最具挑衅性的最新发现之一。

DESCRIPTION (provided by applicant): The long-term goal of the project is to understand the mechanisms underlying the regulation of uterine blood flow during pregnancy. Previous in vivo studies have suggested an important role of estrogen and progesterone in the regulation of uterine blood flow in pregnancy. In addition to the effects on endothelial nitric oxide synthesis/release, the direct effects and mechanisms of the steroid hormones on the adaptation of uterine artery contractility to pregnancy remain poorly understood. Recently, we have demonstrated that PKC and ERK1/2 interact and regulate pressure-induced myogenic tone of resistance-sized uterine arteries, which is significantly attenuated in pregnant animals. Pressure-dependent myogenic contraction is an important physiologic mechanism that regulates basal vascular tone, and is a major contributor to the modulation of blood flow. Our preliminary data showed that physiological relevant concentrations of estrogen and progesterone had direct genomic effects, and up-regulated ERK1/2 and suppressed PKC-mediated myogenic contractions in the uterine artery. The proposed studies will focus on the mechanisms, and test the main hypothesis that the steroid hormones differentially regulate the ERK1/2 and PKC signaling pathways, resulting in a decrease in actin polymerization and myogenic tone of the uterine artery during pregnancy. To test the hypothesis, 3 Specific Aims are formulated, which will determine whether 1) estrogen/progesterone up-regulate ERK1/2 gene expression and suppress PKC activity in the uterine artery, 2) ERK1/2 and PKC differentially regulate actin polymerization and myogenic vascular tone in the uterine artery during pregnancy, and 3) estrogen and progesterone inhibit actin polymerization and suppress vascular tone through the regulation of ERK/PKC pathways in the uterine artery during pregnancy. The studies will be performed in nonpregnant and pregnant ovine uterine arteries in an ex vivo tissue culture model system, and will determine the direct effects of the steroid hormones on gene expression pattern and activities of ERK1/2 and PKC isozymes, actin polymerization, and pressure-induced myogenic contraction in the uterine arteries. The results will provide exciting novel insights into the mechanisms of steroid hormones in the adaptation of uteroplacental circulation during pregnancy, which have obvious clinical implications because the mal-adaptation of uterine circulation to pregnancy is associated with fetal developmental abnormalities and maternal cardiovascular disorders. PUBLIC HEALTH RELEVANCE: Uterine blood flow increases significantly during human pregnancy, which ensures normal fetal development. In addition to growth and remodeling of uterine vasculature, there is a significant decrease in uterine vascular resistance resulting from increased relaxation and decreased contraction of the uterine artery. The mechanisms in adaptation of uterine artery contractility to pregnancy are complex, and are not fully understood. The proposed studies will investigate the molecular mechanisms of steroid hormones in the adaptation of uterine circulation during pregnancy, and will help provide a mechanistic basis for understanding clinical problems associated with mal-adaptation and abnormal pregnancy that lead to many fetal development abnormalities including intrauterine growth restriction, as well as maternal cardiovascular disorders including hypertension in pregnancy. In addition, these studies will provide very useful information in understanding fetal origins of cardiovascular disease, which is one of the most provocative recent findings in modern medicine.