VERGFR-1 in the Uterine Circulation During Pregnancy

描述（由申请人提供）：在怀孕期间，子宫血流量的显著增加是通过血管扩张和反应性改变的复杂综合过程发生的。VEGF （Vascular Endothelial Growth Factor，血管内皮生长因子）和PlGF （Placental Growth Factor，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，它与VEGFR-1受体特异性结合。PlGF-VEGFR-1的故事是令人兴奋的，因为最近的发现揭示了它能够刺激血管扩张和血管舒张，并调节VEGF对VEGFR-2受体的作用。VEGFR-1信号的抑制与子痫前期、胎儿和胎盘重量减少以及子宫循环动脉重塑受损有关。拟议的研究旨在通过解决四个特定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行为：目的1将确定改变的VEGFR-1信号传导对子宫血流和血管重塑的影响。目的2将描述该受体在子宫动静脉中的定位和分子生物学特征，以及其在妊娠和血管大小中的作用，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，以及血管舒张剂分子的分子特性。目的4将确定VEGFR-1激活放大子宫静脉通透性的细胞途径（para- or - trans-cell）和信号机制。这些研究将使用四种大鼠体内病毒过表达模型（sVEGFR-1, sVEGFR-2, PlGF， VEGF）和一种手术子宫角结扎模型，其中植入仅限于子宫一侧，并结合体外评估动脉和静脉的结构变化以及受体调节和信号传导的机制。妊娠期子宫血管的生长、血管舒张和通透性增加都有助于增加子宫血流量。该项目将对子痫前期、子宫血管重构不足和血管活性信号失衡导致血管过度收缩的生理信号通路产生新的认识。公共卫生相关性：本项目是对妊娠期间子宫循环中VEGF/PlGF生长因子家族受体VEGFR-1的生物学作用的研究。这些研究对女性健康具有潜在的重要意义，因为最近发现VEGFR-1的失调与先兆子痫有关。令人惊讶的是，人们对其对子宫血管的作用知之甚少，本项目将确定其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.