Ron Hadas - Department of Biological Regulation, Weizmann Institute, Rehovot, Israel. 
Eran Gershon - Agricultural Research Organization, Volcani Center, Israel. 
Aviad Cohen - Department of Biological Regulation, Weizmann Institute, Rehovot, Israel; Department of Gynecology, Tel Aviv Sourasky Medical Center, Affiliated to the Sackler School of Medicine, Tel Aviv University, Israel.

Ofir Atrakchi - Department of Biological Regulation, Weizmann Institute, Rehovot, Israel. 
Shlomi Lazar - Department of Pharmacology, The Israel Institute for Biological Research, Nes Ziona, Israel. 
Ofra Golani - Department of Life Sciences Core Facilities and. 
Bareket Dassa - Department of Life Sciences Core Facilities and. 
Michal Elbaz - Agricultural Research Organization, Volcani Center, Israel. 
Gadi Cohen - Department of Biological Regulation, Weizmann Institute, Rehovot, Israel. 
Raya Eilam - Department of Veterinary Resources, Weizmann Institute, Rehovot, Israel. 
Nava Dekel - Department of Biological Regulation, Weizmann Institute, Rehovot, Israel.

 
Michal Neeman - Department of Biological Regulation, Weizmann Institute, Rehovot, Israel.

Successful implantation is associated with a unique spatial pattern of vascular remodeling, characterized by profound peripheral neovascularization surrounding a periembryo avascular niche. We hypothesized that hyaluronan controls the formation of this distinctive vascular pattern encompassing the embryo. This hypothesis was evaluated by genetic modification of hyaluronan metabolism, specifically targeted to embryonic trophoblast cells. The outcome of altered hyaluronan deposition on uterine vascular remodeling and postimplantation development were analyzed by MRI, detailed histological examinations, and RNA sequencing of uterine NK cells. Our experiments revealed that disruption of hyaluronan synthesis, as well as its increased cleavage at the embryonic niche, impaired implantation by induction of decidual vascular permeability, defective vascular sinus folds formation, breach of the maternal-embryo barrier, elevated MMP-9 expression, and interrupted uterine NK cell recruitment and function. Conversely, enhanced deposition of hyaluronan resulted in the expansion of the maternal-embryo barrier and increased diffusion distance, leading to compromised implantation. The deposition of hyaluronan at the embryonic niche is regulated by progesterone-progesterone receptor signaling. These results demonstrate a pivotal role for hyaluronan in successful pregnancy by fine-tuning the periembryo avascular niche and maternal vascular morphogenesis.