Induction of uterine vascular remodeling by myometrial stretch

子宫肌层拉伸诱导子宫血管重塑

• 批准号: 8399058
• 负责人: George J Osol
• 金额: $ 18.15万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-15 至 2014-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8399058
• 关键词: Adult; Anatomy; Animal Model; Animals; Architecture; Arteries; Biomechanics; Blood Circulation; Blood Vessels; Chronic; Clinical; Collagen; Continuous Infusion; Cyclic GMP; Deet; Development; Disease; Elastin; Estrogens; Evaluation; Female; Fetal Growth Retardation; Gonadal Steroid Hormones; Growth; Hormonal; Hormones; Horns; Hyperplasia; Hypertrophy; Image; Implant; Indwelling Catheter; Infusion procedures; Injection of therapeutic agent; Intervention; Ischemia; Knowledge; Laboratories; Lead; Ligation; Luteolysis; Matrix Metalloproteinases; Measurement; Medical; Methodology; Modality; Modeling; Molecular; Myometrial; NG-Nitroarginine Methyl Ester; Operative Surgical Procedures; Organ; Pathway interactions; Pattern; Perfusion; Physiological; Physiological Processes; Physiology; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Procedures; Process; Progesterone; Property; Protocols documentation; Rattus; Regulation; Research; Role; Secure; Signal Transduction; Silicones; Stimulus; Stretching; Structure; Surgical Models; Testing; Time; Trees; Uterus; Vascular Smooth Muscle; Vascular remodeling; Veins; Venous; arterial remodeling; base; follow-up; hemodynamics; implantation; in vivo; innovation; insight; instrument; morphometry; novel; novel therapeutics; palliative; pregnant; pressure; prevent; response; time use; transmission process

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.

描述（由申请人提供）：尽管孕产妇子宫血管重塑对于正常的妊娠结局至关重要，但这种重要的生理过程的生理学尚不清楚。这个R21项目的灵感来自我们最近发现的，即在非怀孕状态下大鼠子宫的物理扩张会导致介质动脉和静脉的显着膨胀生长，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，进行性的子宫伸展以模仿妊娠的扩张[AIM 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，并确定通过使用体内NO抑制和分子（ENOS，PKG）和反应性测量值和反应性测量值（ACH，deta-no）在隔离的容器中使用NO-CGMP-PKG信号传导是否有助于其进展[AIM 2]。根据细胞（内皮，血管平滑肌-VSM）和基质（MMP/TIMP；胶原蛋白和弹性蛋白含量）的变化，表征了血管重塑的特征。通过使用定时释放激素颗粒植入卵巢切除动物的基本机制[AIM 3]。由于重塑发生在子宫菌群以外的介质血管中，因此不太可能将拉伸的直接物理传播作为主要刺激。这就提出了一个问题，即器官如何诱导自己的动脉（根据定义，这是其上游）进行改造和生长的问题。基于血管解剖学和生理先例（黄体溶解的机制），我们假定静脉转移是肌层拉伸诱导动脉重塑的途径。将通过开发一种新的手术程序来检验该假设[AIM 4]，该手术方法利用了中循环的结构和血液动力学，从而消除了循环中一部分的静脉影响，从而可以直接评估这种有趣机制的生理重要性。总而言之，我们建议开发两个新的外科手术模型，以帮助研究膨胀的子宫血管重塑，并探索两种新型的生理机制（肌层扩张作为血管生长和静脉信号转移的刺激）。从临床角度来看，这些研究很有价值，因为它们将提供有关生理过程（妊娠期间母体子宫血管重塑）的新见解，这些过程与胎盘在灌注，先兆子痫和宫内腹腔内生长限制（IUGR）有关。反过来，这些知识可能会导致先兆子痫和IUGR的新治疗方式发展 - 两种常见的，严重且病态的胎儿疾病，目前的医疗治疗完全具有姑息性，并且提供唯一可用的治疗方法。