Steroid Hormone Regulation of Angiogenesis--Endometrium Remodeling

类固醇激素对血管生成的调节--子宫内膜重塑

基本信息

批准号：
7633363
负责人：
ROBERT D KOOS
金额：
$ 31.74万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7633363
关键词：
Angiopoietin-1 Angiopoietin-2 Apoptosis Biological Assay Blood Vessels Blood capillaries Cell Death Cells Coculture Techniques Development Differentiation and Growth Disease regression Endometrial Endometrium Endothelial Cells Epithelial Epithelial Cells Estradiol Estrogens Event Figs - dietary Growth Hormones Human In Vitro Infertility Investments Knowledge Laboratories Lead Luteal Phase Maryland Mediating Menstrual cycle Messenger RNA Microvascular Permeability Modeling Neuropilin-1 Ovarian Steroid Hormone Ovariectomy Papio Pericytes Permeability Phosphotransferases Polymerase Chain Reaction Population Positioning Attribute Primates Process Progesterone Protein Tyrosine Kinase Proteins RNA Rattus Recruitment Activity Regulation Relative (related person)Research Personnel Reverse Transcription Role Rosa Serum Site Smooth Muscle Myocytes Stromal Cells System Testing Thrombospondin 1 Tissues Treatment Protocols Tube Universities Uterus Vascular Endothelial Cell Vascular Endothelial Growth Factors Vascular System Vascular remodeling Vascularization angiogenesis capillary failure Implantation hormone regulation implantation in vivo laser capture microdissection migration nonhuman primate protein expression receptor receptor expression steroid hormone vascular bed

项目摘要

Description (provided by applicant): The human endometrium develops new capillaries from existing microvessels, i.e., angiogenesis, which then undergo maturation and remodeling (i.e., investment of microvessels with periendothelial mural cells) into a new vascular network during each menstrual cycle. Improper vascularization of the endometrium may cause implantation failure and infertility. Estrogen and progesterone have pivotal roles in establishing this vascular bed, but their cellular sites and mechanisms of action are incompletely understood. Vascular endothelial growth/permeability factor (VEG/PF), and other angiostimulatory, e.g., angiopoietin-1 (Ang-1), and angioinhibitory, e.g., Ang-2 and thrombospondin-1 (TSP-1), factors interact to control vascular development, remodeling and regression. During the recent SCCPRR project period, we showed that the expression of VEG/PF in glandular epithelial and stromal cells isolated from the endometrium by laser capture microdissection was decreased to low levels by ovariectomy of baboons and increased/restored to normal by estrogen or estrogen and progesterone. Using a cocultivation system, we showed that estrogen in the presence of human endometrial cells stimulated microvascular endothelial cell tube formation. In Study 1 of Project III, we will use the experimental paradigms recently developed in our nonhuman primate baboon model to test the hypothesis that estrogen and/or progesterone regulate the expression of Ang-1, Ang-2, and TSP-1 by glandular epithelial and/or stromal cells and the VEG/PF neuropilin-1 and Ang-1 Tie-2 receptors by vascular endothelial/vascular smooth muscle cells (VSMC) of the endometrium. In Study 2, we will employ a soluble truncated VEG/PF fit-1 receptor (VEG/PF trap) to sequester VEG/PF in vivo in the baboon uterus, to test the hypothesis that VEG/PF mediates the action of estrogen on microvascular permeability, an early step in angiogenesis. In Study 3, a cocultivation system will be used to test the hypothesis that human endometrial VEG/PF mediates estrogen and/or progesterone action on endothelial cell tube formation and Ang-1 mediates estrogen and/or progesterone action on microvascular endothelial cell/VSMC remodeling. Completion of Project III is expected to lead to a critical understanding of the steroid hormone regulation of angiogenesis and vascular remodeling in the human endometrium.

描述（由申请人提供）：人子宫内膜从现有微血管（即血管生成）中发展出新的毛细血管，然后在每个月经周期内经过成熟和重塑（即使用生友好壁细胞细胞的微血管的投资）为新的血管网络。子宫内膜的血管形成不当可能导致植入失败和不育。雌激素和孕激素在建立此血管床中具有关键作用，但是它们的细胞部位和作用机制尚不完全了解。血管内皮生长/渗透率因子（VEG/PF）以及其他血管刺激性，例如Angiopoietin-1（Ang-1）和血管抑制性，例如Ang-2和血栓形成蛋白-1（TSP-1），因子相互作用，可相互作用，以控制血管发育，重建和回归。在最近的SCCPRR项目期间，我们表明，通过激光捕获的微调从子宫内膜分离的腺上皮细胞和基质细胞中VEG/PF的表达降低至低水平，通过雌激素或雌激素和雌激素和雌激素和雌激素和雌激素和雌激素和雌激素增加/恢复为正常。使用共培养系统，我们表明雌激素在存在下人子宫内膜细胞刺激微血管内皮细胞管的形成。在研究1中第三项目，我们将使用最近在非人类灵长类动物中开发的实验范例狒狒模型测试了雌激素和/或孕激素通过腺体上皮和/或间质细胞以及VEG/PF Neuropilin-1和Ang-1 Tie-2受体的雌激素和/或孕酮调节Ang-1，Ang-2和TSP-1的表达，由血管内皮/血管内皮/血管平滑肌细胞（VSMC）。在研究2中，我们将采用可溶性截短的VEG/PF FIT-1受体（VEG/PF TRAP）来隔离狒狒子宫中的体内VEG/PF，以检验veg/pf的假设，即veg/pf介导了雌激素对微血管通讯性的作用，在血管生成中是早期的。在研究3中，将使用一种共培养系统来检验以下假设：人子宫内膜蔬菜/PF介导雌激素和/或孕酮对内皮细胞管形成的作用，而ANG-1介导雌激素和/或孕酮对微血管内皮细胞/VSMC重塑的孕酮作用。预计项目III的完成将导致对人子宫内膜中血管生成和血管重塑的类固醇激素调节的批判性了解。