Fig. 6.

A_2A and NO signaling pathway regulate the expression of VEGF in normal and late-onset pre-eclampsia. In human feto-placental endothelium from normal pregnancy, activation of A_2A adenosine receptor triggers an intracellular pathway involved increased generation of cAMP, activation (serine¹¹⁷⁵ phosphorylation) of nitric oxide synthase (eNOS), and generation of nitric oxide (NO) from L-arginine. Nitric oxide increases mRNA levels of VEGF via unknown (?) mechanism(s), which may include protein nitration. This A_2A-NO-VEGF pathway can lead to a pro-angiogenic behavior of feto-placental endothelium, since it can stimulate cell proliferation/migration and tube formation. In LOPE, this A_2A-mediated intracellular pathway is elevated (⇪), in particular eNOS activation, NO synthesis, and VEGF expression. Upregulation of A_2A-NO-VEGF pathway observed in LOPE may constitute a compensatory mechanism to hypoxia in the placenta