Steroid Hormones and Uterine Vascular Adaptation to Pregnancy

描述（由申请人提供）：该项目的长期目标是了解妊娠期间子宫血流调节的机制。先前的体内研究表明，雌激素和黄体酮在妊娠期子宫血流调节中起重要作用。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性适应妊娠的直接作用和机制尚不清楚。最近，我们已经证明PKC和ERK1/2相互作用并调节压力诱导的阻力大小子宫动脉的肌张力，这种张力在怀孕动物中显着减弱。压力依赖性肌原性收缩是调节基础血管张力的重要生理机制，是调节血流的主要因素。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介导的子宫动脉肌原性收缩。拟开展的研究将重点关注其机制，并验证主要假设，即类固醇激素差异调节ERK1/2和PKC信号通路，导致妊娠期间子宫动脉肌动蛋白聚合和肌原性张力降低。为了验证这一假设，我们制定了3个具体目标，确定1)雌激素/孕激素是否上调子宫动脉ERK1/2基因表达并抑制PKC活性；2)ERK1/2和PKC是否在妊娠期差异调节子宫动脉肌动蛋白聚合和肌源性血管张力；3)雌激素和孕激素是否通过调节妊娠期子宫动脉ERK/PKC通路抑制肌动蛋白聚合和血管张力。该研究将在未怀孕和怀孕的绵羊子宫动脉中进行体外组织培养模型系统，并将确定类固醇激素对子宫动脉中ERK1/2和PKC同工酶的基因表达模式和活性、肌动蛋白聚合和压力诱导的肌原性收缩的直接影响。该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，因为子宫循环对妊娠的不适应与胎儿发育异常和母体心血管疾病有关，因此具有明显的临床意义。

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.