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

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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.