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The angiogenic role of hyaluronic acid in embryo implantation - Roni Hadas

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 by nature 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. Moreover, MRI inspection of mice pregnant with embryos over-expressing hyaluronidase,  the HA degrading enzyme, in their trophoblast cells, showed defective implantation along with increased permeability of blood vessels immediately surrounding the 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 ECM participation in vascular events involved in successful pregnancy further deciphering some pathological processes responsible for implantation failure.

Hyal-2 Over-expression in Embryonic Trophoblast Cells Resulted in Implantation Abnormality
HyaI-2 over-expression in embryonic trophoblast cells. Blastocysts over-expressing Hyal2 and GFP were generated as described in the above scheme (A); Retrieved from pregnant mice at E35, infected with lenti-viruses containing the genes mentioned above (B), then transferred to pseudo-pregnant mice at E2.5. Placental trophoblast cells expressing GFP at E12.5 alongside the embryo (C); Higher magnification of trophoblast giant cells expressing GFP (D). GE T1 weighted images acquired from pregnant mice at E6.5 after administration of macromolecular biotin-BSA-GdDTPA. Morphologically abnormal implantation sites were observed in the treated group over-expressing Hyal2 and GFP (F) in comparison to the control group over-expressing GFP only (E). MRI images were validated using fluorescent microscopy by staining of biotin-BSA- GdDTPA (H, G) respectively. Hyper-permeable blood vessels were observed in the embryonic niche for the treated group (J) as opposed to the control group (I), visualized by staining of the contrast agent 40 minutes after I.V injection.