We measured the Dll4/Notch and HIF-1a-VEGF pathway molecules and evaluated their clinical relevance. The results showed that DLL4 was a vascular regular involved in pregnancy angiogenesis, and that it was regulated by HIF-1a and VEGF during pregnancy progression under hypoxic conditions. Prior to inclusion in the study, all subjects underwent a standard diagnostic work-up to rule out any verifiable cause of missed abortion. The women were examined using ultrasonography for uterine abnormalities, and blood was drawn for testing for chromosomal abnormalities, immunologic factors and infections, with these analyses resulting in an unexplained etiology. The control group consisted of 26 women in early pregnancy with a healthy, viable intrauterine fetus and no prior miscarriage. Fetal cardiac activity and gestational age were confirmed by ultrasound. Studies have shown that a successful pregnancy depended on enough villous angiogenesis, only with this can it supply adequate oxygen and nutrients. In early pregnancy, the development of trophoblast cells is a hypoxic environment, and trophoblast cells are exposed to a relatively low-oxygen environment and the adaption of trophoblast cells to hypoxic environment is the key to successful pregnancy. Missed abortion was associated with severe lowoxygen and less angiogenesis. In our study, we found that HIF-1a was expressed in induced abortion, and significantly up-regulated in missed abortion. During early pregnancy, vasculogenesis is one of the essential steps in appropriate embryonic vascular system. And during the embryonic angiogenesis development, VEGF and their VEGF receptors are the heart of this signaling network. The concept of VEGFR2 as the main mediator of VEGF biological effect has now been generally accepted that it plays a key role in embryonic angiogenesis. This is also confirmed by data on inhibition of angiogenesis upon inactivation of VEGFR2. And it was supposed that negative regulation of the effect of VEGF on vascular endothelial cells rather than mitotic signal transduction might be the main function of VEGFR1. In our study, in induced abortion, VEGF was positively correlated with VEGFR1 and close positively correlated with VEGFR2, and VEGFR1 was also close positively correlated with VEGFR2. Our findings indicated that this balance promotes the angiogenesis to maintenance the normal pregnancy. However, in missed abortion, the balance was interrupted. VEGF was down-regulated and VEGFR1 was elevated, while VEGFR2 was found no significant change, which may contribute to the missed abortion. During pregnancy, with the changes in oxygen levels, placental trophoblast vascular network angiogenesis will change accordingly. Hypoxia is one of the most important factors inducing VEGF expression. VEGF gene expression is up-regulated in hypoxia via the oxygen sensor HIF-1a. Our study showed that HIF-1a was positively correlated with VEGFR2 in induced abortion.
ther investigate the association of Dll4/Notch and HIF1a-VEGF signaling pathways in missed abortion
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