Extracellular Matrix-Mediated Endometrial Decidualization and Angiogenesis

项目摘要 早期妊娠丢失是最常见的早期妊娠并发症，其发病率估计为 ~ 75%。因此，阐明胚胎植入和植入后过程的机制将有助于减少这种不良反应。 妊娠结局。蜕膜化是一个基质细胞增殖和分化的过程， 蜕膜，支持胚胎的生长和生存从植入后通过前胎盘期。 细胞外基质（ECM）重塑和血管生成是与血管生成平行发生的潜在事件。 蜕膜化原纤维胶原是蜕膜中丰富的主要ECM蛋白质组， 内皮细胞和血管壁。然而，它们在子宫内膜蜕膜化、胚胎侵袭和 血管生成是未知的。我们的初步数据表明，纤维状胶原蛋白经历了戏剧性的 与未蜕膜化的着床前子宫内膜相比，蜕膜内的重塑。利用小说 在小鼠模型中，我们提供了令人信服的证据，表明纤维胶原蛋白在 子宫内膜蜕膜化和血管生成。条件性缺失Col 5a 1（V型胶原α 1链） 由于严重的子宫内出血和全部胚胎吸收导致完全妊娠失败。基于 基于这些强有力的初步数据，我们提出了子宫内膜蜕膜化缺陷的特征， 胚胎侵入，导致缺乏Col 5a 1的子宫中的总胚胎吸收（目的1），表征了 Col 5a 1介导的纤维胶原重塑决定了蜕膜化和胚胎发育的进展 生长（目的2），并确定受损的血管生成和破坏的血管重塑是主要的潜在因素 在Col 5a 1条件性敲除小鼠中引起子宫内出血的机制（目的3）。我们将利用 生理学相关的和新的体内模型-子宫特异性Col 5a 1条件性敲除小鼠-以 探讨纤维胶原在子宫内膜蜕膜化和血管生成中的作用。我们还将利用 包括成像技术和体外细胞衍生基质的方法的独特组合。的 本研究结果将有助于我们进一步了解纤维胶原在子宫内膜异位症中的作用。 蜕膜化和血管生成。

Project Summary Early pregnancy loss is the most prevalent early pregnancy complication, and its incidence is estimated to be ~75%. Thus, delineating the mechanisms of peri and post-implantation processes will help reduce this adverse pregnancy outcome. Decidualization, a process of stromal cell proliferation and differentiation for the formation of decidua, supports embryonic growth and survival from post-implantation through pre-placentation period. Extracellular matrix (ECM) remodeling and angiogenesis are underlying events that occur in parallel to the decidualization. Fibrillar collagens are predominant ECM group of proteins which are abundant in the decidua, endothelial cells, and vascular wall. However, their role in the endometrial decidualization, embryo invasion and angiogenesis are not known. Our preliminary data suggests that the fibrillar collagen undergoes dramatic remodeling within the decidua compared to non-decidualized pre-implantation endometrium. Utilizing a novel mouse model, we provide compelling evidence that the fibrillar collagen is playing an indispensable role in endometrial decidualization and angiogenesis. Conditional deletion of Col5a1 (collagen type V alpha 1 chain) resulted in complete pregnancy failure due to severe intrauterine hemorrhage and total embryo resorption. Based on these strong preliminary data, we propose to characterize the defects in endometrial decidualization and embryo invasion which lead to total embryo resorption in the uterus lacking Col5a1(aim 1), characterize the Col5a1-mediated fibrillar collagen remodeling that determines progression of decidualization and embryonic growth (aim 2), and identify impaired angiogenesis and disrupted vascular remodeling as predominant underlying mechanisms that cause intrauterine hemorrhage in Col5a1 conditional knockout mice (aim 3). We will utilize a physiologically relevant and novel in vivo model – uterine specific Col5a1 conditional knockout mice – to interrogate the function of fibrillar collagen in endometrial decidualization and angiogenesis. We will also utilize a unique combination of approaches including imaging techniques and in vitro cell derived matrices. The outcomes of this study will enhance our understanding on the function of fibrillar collagen during endometrial decidualization and angiogenesis.