STEROID HORMONE REGULATION OF ANGIOGENESIS IN ENDOMETRIUM--IMPACT ON FERTILITY

子宫内膜经历了广泛的细胞分化和 新血管的发育，即每一次月经期间的血管生成 为植入做准备的周期。虽然雌激素和黄体酮 已经确立了在新生血管中的作用，潜在的机制 这一进程尚未建立。比生长促进剂 多肽，即血管内皮生长/通透性因子(VEG/PF) 和碱性成纤维细胞生长因子，刺激其他血管生成 系统。因此，目前的基础与临床相结合的研究项目 将在已建立的非人类灵长类动物模型中利用体内方法， 一种基于微载体的与人类共培养系统 以检验雌激素和/或孕激素的假说 通过刺激血管内皮生长因子的表达来调节子宫内膜血管生成 VEG/PR和bFGF及其受体。在研究1中，血管生成， 微血管通透性与血管内皮生长因子的表达和细胞定位 VEG/PF和bFGF及其各自的酪氨酸激酶受体将 在正常月经周期和月经结束后检测到的 卵巢切除和急性或慢性给予雌二醇和/或 孕激素。研究2将使用腺病毒介导的反义 寡核苷酸转移技术阻断VEG/Pf和VEG/Pf的表达 在子宫中检测碱性成纤维细胞生长因子在体内的假说，这些多肽 在子宫内膜血管生成中的重要作用 在狒狒的繁殖力上。研究3将使用微载体 共培养系统，以检验雌激素和/或 孕酮通过以下途径调节人子宫内膜细胞血管生成 模拟VEG/PF和bFGF及其受体的表达。这个 这项研究的目的是将获得的知识转移到 狒狒体内血管生成系统的生理与调控 对人子宫内膜细胞的体外研究。完成这项工作 该项目将为提高我们的理解提供基本的基础 的病因，并在未来的项目年建立更多 女性不孕不育的有效激素治疗方式。

The uterine endometrium undergoes extensive cellular differentiation and development of new blood vessels, i.e. angiogenesis during each menstrual cycle in preparation for implantation. Although estrogen and progesterone have established role in neovascularization, the mechanisms underlying this process have not been established. Specific growth-promoting peptides, i.e. vascular endothelial growth/permeability factor (VEG/PF) and basic fibroblast growth factor (bFGF), stimulate angiogenesis in other systems. Therefore, the present combined basic-clinical research project will utilize in vivo approaches in an established non-human primate model, the baboon, and a microcarrier-based cocultivation system with human endometrial cells to test the hypothesis that estrogen and/or progesterone regulate angiogenesis with the endometrium by stimulating expression of VEG/PR and bFGF and their receptors. In Study 1, angiogenesis, microvascular permeability and expression and cellular localization of VEG/PF and bFGF and their respective tyrosine kinase receptors will be determined in baboons during the normal menstrual cycle and after ovariectomy and the acute or chronic administration of estradiol and/or progesterone. Study 2 will employ an adenovirus-mediated antisense oligonucleotide transfer approach to disrupt the expression of VEG/PF and bFGF in the uterus to test in vivo the hypothesis that these peptides have essential roles upon angiogenesis within the endometrium and consequently upon fertility of the baboon. Study 3 will use a microcarrier cocultivation system to test the hypothesis that estrogen and/or progesterone regulate angiogenesis in human endometrial cells by simulating expression of VEG/PF and bFGF and their receptors. The objective of this study is to transfer the knowledge gained on the physiology and regulation of the angiogenesis system in vivo in the baboon to the study of human endometrial cells in vitro. Completion of this project will provide a fundamental basis for improving our understanding of the etiology of, and establishing in future project years more effective hormonal treatment modalities for, infertility in women.