DESCRIPTION (provided by applicant): Although maternal uterine vascular remodeling is essential for normal pregnancy outcome, the physiology of this important physiological process is not well understood. This R21 project is inspired by our recent discovery that physical distension of the rat uterus in the nonpregnant state leads to significant expansive growth of the mesometrial arteries and veins similar to that seen in pregnancy. We propose to build on this finding by developing an innovative surgical model for inducing controlled, progressive uterine stretch to mimic the distension of pregnancy [Aim 1]. Once established, this model will be used to define the structural and functional parameters of the remodeling process, and to determine whether NO-cGMP-PKG signaling contributes its progression by using in vivo NO inhibition, and molecular (eNOS, PKG) and reactivity measurements (ACh, DETA-NO) in isolated vessels [Aim 2]. Having characterized the vascular remodeling in terms of both cellular (endothelial, vascular smooth muscle - VSM) and matrix (MMP/TIMPs; collagen and elastin content) changes, will then test the hypothesis that the process of arterial and venous expansive growth is amplified by the systemic milieu of pregnancy, and probe for the involvement of sex steroids (estrogen, progesterone) in the underlying mechanism by using timed-release hormone pellets implanted in ovariectomized animals [Aim 3]. Because remodeling occurs in mesometrial vessels that are outside of the uterine corpus, direct physical transmission of stretch as the primary stimulus is unlikely. This begs the question of how an organ can induce its own arteries (which are, by definition, upstream of it) to remodel and grow. Based on the vascular anatomy and physiological precedent (mechanism of luteolysis), we postulate venoarterial transfer to be the pathway by which myometrial stretch induces arterial remodeling. This hypothesis will be tested [Aim 4] by developing a new surgical procedure that takes advantage of the architecture and hemodynamics of the mesometrial circulation to eliminate venoarterial influences in a portion of the circulation, and thus allow a direct evaluation of the physiological importance of this intriguing mechanism. In summary, we propose to develop two new surgical models to help investigate expansive uterine vascular remodeling, and to explore two novel physiological mechanisms (myometrial distension as a stimulus for vessel growth and venoarterial signal transfer) in its genesis. From a clinical standpoint, these studies are valuable because they will provide new insights into a physiological process (maternal uterine vascular remodeling during gestation) whose abrogation is associated with placental under perfusion, preeclampsia and intrauterine growth restriction (IUGR). This knowledge may, in turn, lead to the development of new therapeutic modalities for preeclampsia and IUGR - two common, significant and morbid gestational diseases for which current medical treatment is entirely palliative, and delivery the only available cure.

Maternal uterine vascular growth and remodeling is essential for normal pregnancy outcome, yet, the mechanisms and pathways by which this unique physiological process is regulated are not known. This project is based on the recent discovery that the distension of the uterus in the nonpregnant state induces arterial and venous enlargement that parallels that of pregnancy. We propose to develop and establish a new in vivo surgical model of progressive uterine stretch (Aim 1), to characterize its effect on the vessels (Aim 2), examine the role of pregnancy and female sex steroids in its regulation (Aim 3) and determine whether venoarterial signaling is the pathway by which it is accomplished (Aim 4).