Induction of uterine vascular remodeling by myometrial stretch

描述（由申请人提供）：尽管母体子宫血管重构对正常妊娠结局至关重要，但这一重要生理过程的生理机制尚不清楚。这个R21项目的灵感来自于我们最近的发现，即在非怀孕状态下大鼠子宫的物理膨胀导致与怀孕时相似的系膜动脉和静脉的显著扩张生长。我们建议在这一发现的基础上，开发一种创新的手术模型，以诱导可控的渐进式子宫拉伸来模拟妊娠期的扩张[目的1]。一旦建立，该模型将用于定义重塑过程的结构和功能参数，并通过体内NO抑制以及分离血管中的分子（eNOS， PKG）和反应性测量（ACh, DETA-NO）来确定NO- cgmp -PKG信号是否有助于其进展[Aim 2]。从细胞（内皮、血管平滑肌- VSM）和基质（MMP/TIMPs；胶原和弹性蛋白含量）变化两方面对血管重构进行表征后，将验证动脉和静脉扩张生长过程被妊娠的全身环境放大的假设，并通过植入卵巢切除动物的定时释放激素颗粒，探讨性类固醇（雌激素、黄体酮）在潜在机制中的参与[Aim 3]。由于重塑发生在子宫体外的子宫系膜血管中，因此不太可能将拉伸作为主要刺激的直接物理传递。这就引出了一个问题：一个器官是如何诱导自己的动脉（根据定义，它位于动脉的上游）重塑和生长的。基于血管解剖学和生理先例（黄体溶解机制），我们假设静脉动脉转移是肌层拉伸诱导动脉重构的途径。这一假设将通过开发一种新的外科手术来验证[Aim 4]，该手术利用系膜循环的结构和血流动力学来消除部分循环中的静脉影响，从而可以直接评估这一有趣机制的生理重要性。综上所述，我们建议建立两种新的手术模型来帮助研究扩张性子宫血管重构，并探索其发生的两种新的生理机制（肌层扩张作为血管生长和静脉动脉信号传递的刺激）。从临床角度来看，这些研究具有重要的价值，因为它们将为妊娠期间母体子宫血管重构的生理过程提供新的见解，其废除与胎盘灌注、子痫前期和宫内生长受限（IUGR）有关。这一知识反过来可能导致开发新的治疗方式来治疗先兆子痫和IUGR，这两种常见的、严重的和病态的妊娠疾病，目前的医学治疗完全是姑息性的，分娩是唯一可用的治疗方法。

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. PUBLIC HEALTH RELEVANCE: 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).