Induction of uterine vascular remodeling by myometrial stretch

描述(申请人提供)：尽管母体子宫血管重塑对正常妊娠结局至关重要，但这一重要生理过程的生理学还不是很清楚。这个R21项目的灵感来自我们最近的发现，即非怀孕状态下的大鼠子宫的物理扩张会导致子宫系膜动脉和静脉的显着扩张，类似于怀孕时的情况。我们建议在这一发现的基础上，开发一种创新的手术模型，以诱导受控的、渐进的子宫拉伸来模拟妊娠的扩张[目标1]。一旦建立，这个模型将被用来确定重塑过程的结构和功能参数，并通过在体内使用NO抑制以及在分离的血管中测量分子(eNOS，PKG)和反应性(ACh，DETA-NO)来确定NO-cGMP-PKG信号是否参与其进展[目标2]。在从细胞(内皮、血管平滑肌-VSM)和基质(基质/TIMPs；胶原和弹性蛋白含量)的变化方面表征了血管重构之后，他们将检验动脉和静脉的扩张生长过程被妊娠的全身环境放大的假设，并通过使用植入卵巢切除动物体内的定时释放激素颗粒来探索性类固醇(雌激素、孕酮)在潜在机制中的参与[目标3]。因为重塑发生在子宫体外的子宫系膜血管，拉伸作为主要刺激的直接物理传递是不太可能的。这就引出了一个问题，一个器官如何才能诱导它自己的动脉(根据定义，它是它的上游)重塑和生长。根据血管解剖学和生理学先例(黄体溶解的机制)，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程序来验证[目标4]，该手术程序利用子宫系膜循环的结构和血流动力学来消除部分循环中的静脉-动脉影响，从而允许直接评估这一有趣机制的生理重要性。综上所述，我们建议建立两个新的手术模型来帮助研究扩张性子宫血管重塑，并探索其发生的两个新的生理机制(子宫肌层扩张作为血管生长的刺激和静脉动脉信号传递)。从临床的角度来看，这些研究是有价值的，因为它们将为一个生理过程(妊娠期母体子宫血管重塑)提供新的见解，该过程的取消与胎盘灌注不足、先兆子痫和宫内生长受限(IUGR)相关。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宫内发育迟缓--这两种常见、重大和病态的妊娠期疾病，目前的药物治疗完全是姑息性的，并且提供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.