Extracellular Matrix-Mediated Endometrial Decidualization and Angiogenesis

项目摘要 早孕丢失是最常见的早孕并发症，其发病率估计为 ~75%。因此，描述植入期间和植入后过程的机制将有助于减少这种不利因素。 妊娠结局。蜕膜化是基质细胞增殖和分化形成的过程 从植入后到胎盘前期，蜕膜支持胚胎的生长和存活。 细胞外基质(ECM)重塑和血管生成是与 蜕膜化。纤维性胶原蛋白是蜕膜中丰富的细胞外基质蛋白质组， 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 血管生成尚不清楚。我们的初步数据表明，纤维状胶原蛋白经历了戏剧性的 蜕膜内重构与非蜕膜化植入前子宫内膜的比较。利用一本小说 小鼠模型，我们提供了令人信服的证据表明，纤维状胶原在 子宫内膜蜕膜化与血管生成。COL5a1(V型胶原α1链)的条件性缺失 因严重宫内出血和胚胎完全吸收导致完全妊娠失败。基座 根据这些强有力的初步数据，我们建议对子宫内膜蜕膜化和子宫内膜化的缺陷进行表征。 胚胎侵入导致子宫中缺乏Col5a1(目标1)的完全胚胎吸收，其特征是 Col5a1介导的纤维状胶原重塑决定蜕膜化和胚胎的进展 生长(目标2)，并确定血管生成受损和血管重塑障碍是主要的潜在原因 在COL5a1条件性基因敲除小鼠中导致宫内出血的机制(目标3)。我们将利用一个 生理上相关的新型体内模型-子宫特异性Col5a1条件性基因敲除小鼠-TO 探讨纤维性胶原在子宫内膜蜕膜形成和血管生成中的作用。我们还将利用 一种独特的方法组合，包括成像技术和体外细胞衍生基质。这个 这项研究的结果将加深我们对纤维胶原在子宫内膜中的作用的理解 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.