Studies are proposed to examine the role of a critical local factor, vascular endothelial growth factor (VEGF) in the response to chorionic gonadotropin (CG) during controlled ovulation cycles (COS) in rhesus macaques, an excellent non-human primate model of women's reproductive health. The experiments proposed in this R21 application should discern between the VEGF-dependent and independent actions of CG resulting in early and late onset symptoms of ovarian hyperstimulation syndrome (OHSS). The contribution of CG-induced VEGF to induce the marked ovarian/systemic hyperpermeability associated with onset of OHSS has not been directly investigated in primates. Women with polycystic ovarian syndrome (PCOS~ approximately 5-10% of women in the USA) are at high risk for developing OHSS during COS for infertility treatments~ avoidance of OHSS during COS is a major concern for infertility specialists. To date, investigations into the relationship betwen vascular structure/function of reproductive tissues and actions of local angiogenic factors have been indirect or static in nature involving single observations after tissue removal. The PI has applied sensitive, minimally invasive techniques enabling repeated measurements of vascular structure-function in the ovaries and uterus of nonhuman primates. Contrast enhanced-Ultrasound (CE-US) and Dynamic Contrast Enhanced- Magnetic Resonance Imaging (DCE-MRI) protocols allow direct quantification of blood flow/volume and tissue permeability of reproductive tissues. Notably, it is possible to simultaneously apply the proposed novel imaging approaches to the uterus, as well as the ovary, to discern the VEGF-dependent versus-independent effects of CG on vascular dynamics in primates. In addition to quantifying the effects of VEGF neutralization on vascular function of reproductive tissues, effects on other angiogenic factors (angiopoietins, ANGPTs) will be quantified as possible therapeutic interventions for OHSS. The results of these experiments will guide future studies investigating novel molecules affecting both ovarian and uterine/systemic vascular function by both imaging and molecular methods. These techniques can be used to identify and evaluate specific therapeutic interventions for women at risk for OHSS and infertility.
This project will further our understanding into the actions of CG and VEGF/ANGPT-1&-2 on the vascular remodeling that occurs in the primate corpus luteum and endometrium during physiologic and pathologic conditions. Novel non-invasive methods to quantify blood flow/volume and vascular permeability, such as contrast enhanced-ultrasound and dynamic contrast enhanced-magnetic resonance imaging, not only have research applications, but will also provide new insight into diagnosis and efficacy of therapies in women with disorders of the ovarian vasculature such as ovarian hyperstimulation syndrome (OHSS).