Ron Hadas, Aviad Cohen, Nava Dekel, Michal Neeman 

The Weizmann Institute, Rehovot

Implantation, a critical step in the establishment of pregnancy, is immediately followed by a marked increase in the permeability and density 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 may be involved in vascular modifications associated with implantation. Our experiments revealed interesting alterations in HA distribution in the endometrium from the onset of implantation. In addition, we found an increase in HA fragmentation during early pregnancy. Moreover, substantial changes in the expression profile of genes encoding for HA synthesis and degrading enzymes as well as in the distribution of their protein products were observed in the implantation site during early pregnancy. Such gene and protein modifications were also noticed in the HA receptors as well as in some specific ECM stabilizing proteins. Functional MRI inspection of HA synthesis inhibitor 6-diazo-5-oxo-1-norleucine (DON) treated pregnant mice, on embryonic day 6.5, showed a marked increase in decidual blood vessel permeability and accumulation of blood in close proximity to the implanting embryo. Taking these observations into account, we suggest that HA uterine metabolism has a pivotal role in vascular development and remodeling during embryo implantation in mice. Our study will potentially shed light on the vascular events involved in successful pregnancy further deciphering some pathological processes responsible for implantation failure.