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.