UTERINE VASCULAR RESPONSE TO STEROID SIGNALING

Summary

Principal Investigator: IRA MARK BERNSTEIN
Abstract: The maternal vascular transformation required for successful pregnancy is initiated during the menstrual cycle by a coordinated series of hemodynamic adaptations that appear to be endocrinologically mediated. These events include a decrease in uterine artery vascular impedance and an increase in uterine blood flow that set the stage for implantation and trophoblast development. The failure of this uterine vascular response is associated with specific reproductive inadequacy, including infertility, fetal growth restriction and pre-eclampsia. While estrogen and progesterone have been clearly implicated as signals mediating the adaptive hemodynamic responses, the extent to which these steroids are both necessary and sufficient as primary signals in the human is unknown. Additionally, the mechanisms by which estrogen and progesterone influence the uterine vasculature are unknown. This project is focused on defining, in humans, changes in the uterine and systemic circulation that occur through the menstrual cycle. Specific hormonal effects within the menstrual cycle will be examined as a function of add-back estrogen and progesterone in women with drug induced ovarian suppression. These responses will be individually compared to spontaneous ovulatory cycles. We intend to demonstrate: 1) that the uterine vascular response is unique and distinguishable from the systemic response through the menstrual cycle, 2) that these (both uterine and systemic) responses result specifically from the action of estrogen and progesterone. 3) that estrogen and progesterone influence uterine artery hemodynamics by their effect on endometrial vascular growth via co-regulation of VEGF and VEGF receptors, including neuropilin, the most recently described VEGF receptor. 4) that endogenous steroid responses can be reproduced using an ovarian suppression model with hormonal add-back validating a powerful research technique. To show this we will measure, using Doppler ultrasound, the changes in uterine artery impedance and blood flow as well as the changes in systemic vascular resistance and cardiac output that attend the menstrual cycle, while simultaneously examining the endometrium via biopsy. We will assess, through this unique human model, the isolated and inter-related effects of the specific signal (estrogen and progesterone), with the effector (VEGF), and the responses (angiogenesis, vascular remodeling).
Funding Period: 1999-07-06 - 2004-06-30
more information: NIH RePORT