Ron Hadas1, Aviad Cohen1, Eran Gershon2, Ofir Atrakchi1, Shlomi Lazar3, Raya Eilam-Altstadter4, Nava Dekel1 and Michal Neeman1
1 Department of Biological Regulation, Weizmann Institute, Israel
2 Agricultural Research Organization, Volcani Center, Israel
3 Biological research Institute Nes Ziona, Israel
4 Department of Veterinary Resources, Weizmann Institute, Israel
Embryo implantation, a critical step in the establishment of pregnancy, is immediately followed by a marked increase in the permeability of the uterine blood vessels. Hyaluronic acid (HA) has been reported to participate in the regulation of vascular development in a number of physiological processes. Specifically, high molecular weight HA has been shown to inhibit angiogenesis, whereas its enzymatic degradation products are pro-angiogenic. On the basis of this information, we hypothesized that HA is involved in vascular modifications associated with implantation.
Our experiments revealed that HA deposition and degradation correlates with vascular remodeling in the implantation site during early pregnancy. Moreover, extensive changes in the distribution of HA synthesis and degrading enzymes were observed during implantation. Functional MRI inspection of pregnant mice, carrying embryos, the trophoblast cells of which over-express HA degrading enzyme, showed defective implantation. Specifically, an increased permeability of blood vessels surrounding the embryo accompanied by infiltration of endothelial cells ultimately resulted in multiple embryo resorptions. Interestingly, over-expression of HA synthesizing enzyme, in trophoblast cells, resulted in the termination of pregnancy associated with an opposite phenotype, i.e, reduced permeability of blood vessels in the embryonic niche and a decrease in fractional blood volume.
Taking these observations into account, we suggest that HA uterine metabolism has a pivotal role in vascular remodeling essential for successful embryo implantation in mice. Our study sheds light on the participation of the extracellular matrix in the complex chain of vascular events involved in successful pregnancy, thus deciphering new components responsible for gestational disturbances.