Steroid Hormone Regulation of Angiogenesis in Uterus

类固醇激素对子宫血管生成的调节

• 批准号: 6931411
• 负责人: ROBERT D KOOS
• 金额: $ 19.89万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-20 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6931411
• 关键词: angiogenesis; baboons; cooperative study; endometrium; estradiol; estrogens; hormone regulation /control mechanism; human tissue; immunocytochemistry; laser capture microdissection; mixed tissue /cell culture; nonsurgical revascularization; polymerase chain reaction; progesterone; steroid hormone; vascular endothelial growth factors; vascular endothelium permeability

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(申请人提供)：在每个月经周期，人类子宫内膜从现有的微血管中发育出新的毛细血管，即血管生成，然后经历成熟和重塑(即微血管与内皮周围壁细胞的投资)进入新的血管网络。子宫内膜血管形成不当可能导致着床失败和不孕。雌激素和孕激素在建立这一血管床中起着关键作用，但它们的细胞位置和作用机制尚不完全清楚。血管内皮生长/渗透因子(VEG/PF)和其他血管刺激因子，如血管生成素-1(Ang-1)，以及血管抑制因子，如Ang-2和血栓反应蛋白-1(TSP-1)，这些因子相互作用，控制血管的发育、重塑和退化。在最近的SCCPRR项目期间，我们发现，激光捕获显微切割分离的子宫内膜腺上皮和间质细胞中，卵巢切除后VEG/PF的表达降低到较低水平，而雌激素或雌激素和孕激素则增加/恢复到正常水平。使用共培养系统，我们证明了雌激素的存在 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 项目三，我们将使用最近在我们的非人类灵长类动物中开发的实验范式 本实验旨在验证雌激素和/或孕激素调节腺上皮和/或间质细胞Ang-1、Ang-2和TSP-1的表达，以及子宫内膜血管内皮细胞/血管平滑肌细胞(VSMC)调节腺上皮和/或间质细胞的VEG/PF Neuropilin-1和Ang-1 Tie-2受体的假说。在研究2中，我们将使用可溶截短的VEG/PF Fit-1受体(VEG/PF TRAP)将VEG/PF活体隔离在狒狒子宫中，以验证VEG/PF介导雌激素对微血管通透性的作用的假说，这是血管生成的早期步骤。在研究3中，将使用共培养系统来检验假设，即人子宫内膜VEG/PF介导雌激素和/或孕酮对内皮细胞管形成的作用，Ang-1介导雌激素和/或孕酮对微血管内皮细胞/VSMC重构的作用。项目III的完成有望导致对类固醇激素对人类子宫内膜血管生成和血管重塑的调控有重要的理解。