Increased uterine vascular permeability and angiogenesis at the sites of implantation are critical to the process of implantation. Are critical to the process of implantation. Prostaglandins (PGs), because of their vasoactive and pro-angiogenic nature, are implicated in these events. The cyclooxygenase (COX) system, the rate-limiting step in PG synthesis, exist in two isoforms: COX-1 and COX-2. We have established that COX-2 derived prostacyclin (PGI2) via activation of PPARdelta is essential for implantation. We hypothesize that COX-2-PGIs-PPARdelta signaling participates in uterine vascular permeability and angiogenesis required for implantation via coordinated interactions of vascular endothelial growth factor (VEGF) with angiopoietins. Thus, implantation failure in COX-2 deficient mice may result from aberrant uterine expression of the VEGF and/or angiopoietin systems.
Our specific aims are to determine in the mouse: (1) Expression of angiopoietins, Tie-2 receptor and their interactions in the peri-implantation mouse uterus; (2) Status of VEGF and angiopoietin systems in the peri-implantation uteri of COX-2(-/-) mice; (3) Effects of deficiency of COX-2 on uterine vascular responses and angiogenesis; and (4) COX-2-PGI2-PPARdelta signaling in uterine angiogenesis during implantation and decidualization. The results obtained from these specific aims will provide valuable and comprehensive new information (i) regarding the participation of uterine vascular permeability and angiogenesis during implantation and (ii) whether COX-2 derived PGI2 signaling via activation of PPARdelta directly influence the uterine VEGF and/or angiopoietin systems during implantation. Experimental approaches will include the use of mutant mice, RT-PCR Southern, Northern and in situ hybridization, immunohistochemistry, cross-linking, Western blotting, embryo transfers and cultures. The results of this investigation will aid in alleviating female infertility and prevention of abnormal development in humans.
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