Hyaluronan control of the primary vascular barrier during early mouse pregnancy is mediated by uterine NK cells
Ron Hadas, Eran Gershon, Aviad Cohen, Ofir Atrakchi, Shlomi Lazar, Ofra Golani, Bareket Dassa, Michal Elbaz, Gadi Cohen, Raya Eilam, Nava Dekel, Michal Neeman
Ron Hadas, Eran Gershon, Aviad Cohen, Ofir Atrakchi, Shlomi Lazar, Ofra Golani, Bareket Dassa, Michal Elbaz, Gadi Cohen, Raya Eilam, Nava Dekel, Michal Neeman
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Research Article Angiogenesis Reproductive biology

Hyaluronan control of the primary vascular barrier during early mouse pregnancy is mediated by uterine NK cells

Abstract

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.

Authors

Ron Hadas, Eran Gershon, Aviad Cohen, Ofir Atrakchi, Shlomi Lazar, Ofra Golani, Bareket Dassa, Michal Elbaz, Gadi Cohen, Raya Eilam, Nava Dekel, Michal Neeman

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Figure 6

Detrimental decidual hypervascularity and breach of the maternal-embryo barrier is induced by trophectoderm Hyal-2 overexpression.

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Detrimental decidual hypervascularity and breach of the maternal-embryo ...
(A) Ectopic presence of newly formed maternal blood vessels in the embryonic niche was observed in dams carrying Hyal-2 OEx embryos (n = 5 dams). (B) GE-T1–weighted MRI images of decidua, acquired from pregnant mice at E6.5, 3 minutes after administration of biotin-BSA-GdDTPA; white arrows point at implantation sites. (C–E) Linear regression plots from DCE MRI analysis. Decidual blood volume fraction (fBV; 0.023 ± 0.01 [control]; 0.072 ± 0.009 [overexpression], P = 0.0005) and permeability (PS; 0.00092 ± 0.0003; 0.0074 ± 0.0031, P = 0.09) were calculated from DCE MRI (n = 5 dams 13 implantation sites in control; 6 dams 24 implantation sites in Hyal-2 OEx). (F and G) Increased levels of VEGF-A and VEGFR-2 in decidua harvested at E6.5 (n = 3 dams, 2 implantation sites from each group). (H) Increased VEGFR-2 expression on decidual vessels in mesometrial orientation, as well as in cytotrophoblast cells, in Hyal-2 OEx foster dams (n = 4 dams in each group). (I) Declined VEGFR-3+ VSFs endothelial expression, demonstrated by immunofluorescence (n = 3 dams, 6 implantation sites from each group). (J) Hyperpermeable blood vessels in the embryonic niche were visualized by staining of biotin-BSA-GdDTPA, 40 minutes after intravenous injection (n = 5 dams). (K) Increased MMP-9 levels in E6.5 trophoblast cells OEx Hyal-2 (n = 5 dams in each group). (L) Quantification of MMP-9 expression in E6.5 decidua by immunofluorescence of histological sections (1.858-fold change ± 0.14 [control]; 0.25 [overexpression]; P = 0.01) (n = 5 dams in each group). (M) Increased levels of pro MMP-9 and mature MMP-9 in decidua harvested at E6.5 (n = 3 dams, 2 implantation sites in each group). The statistical analysis applied was Student’s t test (D, E, and L).