VERGFR-1 in the Uterine Circulation During Pregnancy

怀孕期间子宫循环中的 VERGFR-1

• 批准号: 7678529
• 负责人: George J Osol
• 金额: $ 37.91万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7678529
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Affect; Agonist; Animals; Area; Arteries; Binding; Biological; Blood Circulation; Blood Vessels; Blood flow; Bromodeoxyuridine; Calcium; Caliber; Cannulations; Cell Separation; Complex; Coupled; Estrogen Replacements; Estrogens; Family; Fura-2; Goals; Gonadal Steroid Hormones; Growth; Growth Factor; Horns; Hypertrophy; Immunohistochemistry; In Vitro; Individual; Infusion Technique; Injection of therapeutic agent; Investigation; Ligands; Ligation; Measurement; Measures; Mediating; Membrane; Membrane Potentials; Methodology; Methods; Microelectrodes; Microspheres; Mitotic; Modeling; Molecular; Molecular Biology; Molecular Biology Techniques; Myometrial; Nitric Oxide; Operative Surgical Procedures; Organ Culture Techniques; Ovariectomy; Pathway interactions; Permeability; Physiological; Placenta; Placental Growth Factor; Placentation; Play; Potassium Channel; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Process; Progesterone; Prostaglandins; Proteins; Rattus; Regulation; Relative (related person); Reverse Transcriptase Polymerase Chain Reaction; Role; Series; Side; Signal Pathway; Signal Transduction; Structure of uterine vein; System; Techniques; Testing; Thick; Tracer; Transmission Electron Microscopy; Uterus; Vascular Endothelial Growth Factor B; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vascular Smooth Muscle; Vascular remodeling; Vasodilation; Vasodilator Agents; Veins; Venous; Video Microscopy; Viral; Weight; Western Blotting; Women' s Health; arterial remodeling; attenuation; base; feeding; fetal; implantation; in vivo; insight; myometrium; overexpression; pregnant; public health relevance; radial artery; receptor; receptor expression; response; shear stress; solute; synergism; vasoconstriction

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.

描述（由申请人提供）：在怀孕期间，子宫血流的大幅增加是通过复杂而综合的血管增大过程和反应性改变的过程。 VEGF（血管内皮生长因子）和PLGF（胎盘生长因子）是多效生长因子，其血管作用由两个主要受体亚型介导：VEGFR-1和VEGFR-2。 PLGF由胎盘产生和分泌，与VEGF不同，与VEGFR-1受体特别结合。鉴于最近的发现揭示了其刺激血管增大和血管舒张的能力，并调节VEGF对VEGFR-2受体的作用，因此PLGF-VEGFR-1故事令人兴奋。 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的动脉重塑有关。拟议的研究试图了解妊娠如何通过解决四个具体目标来影响VEGFR-1激活的信号传导和功能下游动作：AIM 1将定义VEGFR-1信号改变对子宫血流和血管重塑的影响。 AIM 2将表征该受体在子宫动脉和静脉中的定位和分子生物学与妊娠和血管大小的关系，并确定剪切应力和雌激素如何影响其表达。 AIM 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，以及血管扩张剂分子的分子认同。 AIM 4将确定vegfr-1激活放大子宫静脉渗透性的细胞途径（与跨细胞）和信号传导机制。四只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的一侧，并将用于这些研究，并结合在动脉和静脉和机械下的体外评估，并与机械化和静脉内的结构变化相结合。子宫血管的生长，血管舒张和增加的渗透性都有助于妊娠期间子宫血流的增加。该项目将产生对生理信号通路的新见解，该生理信号传导途径与子痫前期有关，子宫血管重塑不足以及血管活性信号的失衡不足，这有利于过量的血管收缩。 公共卫生相关性：该项目是对怀孕期间子宫循环中VEGFR-1的生物学作用（VEGFR-1（VEGFR-1）的生物学作用。这些研究可能对妇女的健康很重要，因为VEGFR-1的失调最近与先兆子痫有关。令人惊讶的是，它对子宫血管的作用知之甚少，该项目将决定妊娠期间介导子宫血管变化的机制。