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尚未得到很好的理解。这个R21项目的灵感来自于我们最近的发现，即大鼠子宫在非妊娠状态下的物理扩张导致子宫系膜动脉和静脉的显着扩张性生长，类似于妊娠中所见。我们建议通过开发一种创新的手术模型来建立这一发现，以诱导受控的、渐进的子宫牵拉来模拟妊娠扩张[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，并通过使用体内NO抑制和分离血管中的分子（eNOS，PKG）和反应性测量（ACh，ACH-NO）来确定NO-cGMP-PKG信号传导是否有助于其进展[目的2]。在描述了血管重塑的细胞学特征后，（内皮、血管平滑肌- VSM）和基质（MMP/TIMPs;胶原蛋白和弹性蛋白含量）的变化，然后将检验动脉和静脉扩张生长的过程被妊娠的全身环境放大的假设，并探讨性类固醇的参与（雌激素，孕激素）的潜在机制，通过使用定时释放激素丸植入卵巢切除动物[目的3]。由于重塑发生在子宫体外的子宫系膜血管中，因此不太可能将牵拉作为主要刺激直接物理传递。这就引出了一个问题，即器官如何诱导自己的动脉（根据定义，动脉是器官的上游）重塑和生长。基于血管解剖学和生理学先例（黄体溶解机制），我们假设静脉动脉转移是子宫肌层牵拉诱导动脉重构的途径。将通过开发一种新的外科手术来测试这一假设[目的4]，该手术利用子宫系膜循环的结构和血液动力学来消除部分循环中的静脉动脉影响，从而允许直接评价这一有趣机制的生理重要性。总之，我们建议开发两种新的手术模型，以帮助调查扩张性子宫血管重塑，并探讨其发生的两种新的生理机制（子宫肌层扩张作为血管生长和静脉动脉信号传递的刺激）。从临床的角度来看，这些研究是有价值的，因为它们将提供新的见解的生理过程（妊娠期间母体子宫血管重塑），其废除与胎盘灌注不足，先兆子痫和宫内生长受限（IUGR）。这些知识反过来可能导致开发用于先兆子痫和IUGR的新治疗方式-这两种常见的，重要的和病态的妊娠疾病，目前的医学治疗完全是姑息性的，并且递送是唯一可用的治愈方法。 公共卫生相关性：母体子宫血管的生长和重塑对正常妊娠结局至关重要，然而，调节这一独特生理过程的机制和途径尚不清楚。这个项目是基于最近的发现，即在非妊娠状态下子宫的扩张会导致动脉和静脉的扩张，这与妊娠相似。我们建议开发和建立一种新的渐进性子宫牵张的体内手术模型（目的1），以表征其对血管的影响（目的2），研究妊娠和女性性类固醇在其调节中的作用（目的3），并确定静脉动脉信号传导是否是完成的途径（目的4）。

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).