VERGFR-1 in the Uterine Circulation During Pregnancy

描述（由申请人提供）：妊娠期间，通过血管扩张和反应性改变的复杂综合过程，子宫血流量显著增加。VEGF（血管内皮生长因子）和PlGF（胎盘生长因子）是多效性生长因子，其血管作用由两种主要受体亚型：VEGFR-1和VEGFR-2介导。PlGF由胎盘产生和分泌，与VEGF不同，PlGF特异性结合VEGFR-1受体。PlGF-VEGFR-1的故事是令人兴奋的，因为最近的发现揭示了其刺激血管扩张和血管舒张的能力，并调节VEGF对VEGFR-2受体的作用。VEGFR-1信号传导的抑制与先兆子痫、胎儿和胎盘重量降低以及子宫循环的动脉重塑受损相关。拟议的研究旨在通过解决四个具体目标来了解妊娠如何影响VEGFR-1激活的信号传导和功能下游作用：目标1将定义改变的VEGFR-1信号传导对子宫血流和血管重塑的影响。目的2将描述这种受体在子宫动脉和静脉中的定位和分子生物学特征，作为妊娠和血管大小的函数，并确定剪切应力和雌激素如何影响其表达。目的3将阐明VEGFR-1激活产生动脉和静脉血管舒张的机制，重点是钾通道参与膜超极化，以及血管舒张分子的分子身份。目的4将确定VEGFR-1激活放大子宫静脉通透性的细胞途径（帕拉细胞与跨细胞）和信号传导机制。四种大鼠体内病毒过表达模型（sVEGFR-1、sVEGFR-2、PlGF、VEGF）和手术子宫角结扎模型（其中植入仅限于子宫一侧）将用于这些研究，并结合动脉和静脉结构变化的体外评估以及受体调节和信号传导的潜在机制。妊娠期子宫血管的生长、血管扩张和通透性增加都有助于增加子宫血流量。该项目将产生对生理信号通路的新见解，其异常与先兆子痫，子宫血管重塑不足以及有利于过度血管收缩的血管活性信号失衡有关。 公共卫生相关性：该项目是研究妊娠期间子宫循环中VEGF/PlGF生长因子家族的受体VEGFR-1的生物学作用。这些研究对妇女的健康可能很重要，因为最近发现VEGFR-1的失调与先兆子痫有关。令人惊讶的是，人们对它对子宫血管的作用知之甚少，这个项目将确定它在妊娠期间介导子宫血管变化的机制。

DESCRIPTION (provided by applicant): During pregnancy, a profound increase in uterine blood flow occurs via a complex and integrated process of vascular enlargement and altered reactivity. VEGF (Vascular Endothelial Growth Factor) and PlGF (Placental Growth Factor) are pleiotropic growth factors whose vascular actions are mediated by two dominant receptor subtypes: VEGFR-1 and VEGFR-2. PlGF is produced and secreted by the placenta and, unlike VEGF, binds specifically to the VEGFR-1 receptor. The PlGF-VEGFR-1 story is exciting in view of recent findings that reveal its ability to stimulate vessel enlargement and vasodilation, and to modulate the actions of VEGF on the VEGFR-2 receptor. Inhibition of VEGFR-1 signaling is associated with preeclampsia, reduced fetal and placental weights and compromised arterial remodeling of the uterine circulation. The proposed studies seek to understand how gestation affects the signaling and functional downstream actions of VEGFR-1 activation by addressing four Specific Aims: Aim 1 will define the effects of altered VEGFR-1 signaling on uterine blood flow and vascular remodeling. Aim 2 will characterize the localization and molecular biology of this receptor in uterine arteries and veins as a function of gestation and vessel size, and determine how shear stress and estrogen affect its expression. Aim 3 will elucidate the mechanisms by which VEGFR-1 activation produces arterial and venous vasodilation, with a focus on potassium channel involvement in membrane hyperpolarization, and on the molecular identity of the vasodilator molecules. Aim 4 will determine the cellular pathway (para- vs. trans-cellular) and signaling mechanism by which VEGFR-1 activation amplifies uterine venous permeability. Four rat in vivo viral overexpression models (sVEGFR-1, sVEGFR-2, PlGF, VEGF) and a surgical uterine horn ligation model, in which implantation is restricted to one side of the uterus, will be used for these studies and combined with in vitro assessment of structural changes in arteries and veins, and of mechanisms underlying receptor regulation and signaling. The growth, vasodilation and increased permeability of uterine vessels all contribute to increasing uterine blood flow during gestation. This project will generate new insights into a physiological signaling pathway whose aberrance has been implicated in preeclampsia, insufficient uterine vascular remodeling, and an imbalance of vasoactive signals favoring excessive vasoconstriction. PUBLIC HEALTH RELEVANCE: This project is an investigation of the biological actions of VEGFR-1, a receptor for the VEGF/PlGF growth factor family, in the uterine circulation during pregnancy. These studies are potentially important to women's health because dysregulation of VEGFR-1 has recently been associated with preeclampsia. Surprisingly little is known about its actions on the blood vessels of the uterus, and this project will determine the mechanisms by which it mediates uterine vascular changes during gestation.