Adenosine A(2A) receptor regulates expression of vascular endothelial growth factor in feto-placental endothelium from normal and late-onset pre-eclamptic pregnancies

作者：Acurio Jesenia; Herlitz Kurt; Troncoso Felipe; Aguayo Claudio; Bertoglia Patricio; Escudero Carlos^*

来源：Purinergic Signalling, 2017, 13(1): 51-60.

DOI：10.1007/s11302-016-9538-z

• Adenosine
• A(2A)
• Angiogenesis
• Pre-eclampsia
• Nitric oxide
• VEGF

We aim to investigate whether A(2A)/nitric oxide-mediated regulation of vascular endothelial growth factor (VEGF) expression is impaired in feto-placental endothelial cells from late-onset pre-eclampsia. Cultures of human umbilical vein endothelial cells (HUVECs) and human placental microvascular endothelial cells (hPMECs) from normal and pre-eclamptic pregnancies were used. Assays by using small interference RNA (siRNA) for A(2A) were performed, and transfected cells were used for estimation of messenger RNA (mRNA) levels of VEGF, as well as for cell proliferation and angiogenesis in vitro. CGS-21680 (A(2A) agonist, 24 h) increases HUVEC and hPMEC proliferation in a dose response manner. Furthermore, similar to CGS-21680, the nitric oxide donor, S-nitroso-N-acetyl-penicillamine oxide (SNAP), increased cell proliferation in a dose response manner (logEC(50) 10(-9.2) M). In hPMEC, CGS-21680 increased VEGF protein levels in both normal (similar to 1.5-fold) and pre-eclamptic pregnancies (similar to 1.2-fold), an effect blocked by the A(2A) antagonist, ZM-241385 (10(-5) M) and the inhibitor of NO synthase, N (omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME). Subsequently, SNAP partially recovered cell proliferation and in vitro angiogenesis capacity of cells from normal pregnancies exposed to siRNA for A(2A). CGS-21680 also increased (similar to 1.5-fold) the level of VEGF mRNA in HUVEC from normal pregnancies, but not in pre-eclampsia. Additionally, transfection with siRNA for A(2A) decrease (similar to 30 %) the level of mRNA for VEGF in normal pregnancy compared to untransfected cells, an effect partially reversed by co-incubation with SNAP. The A(2A)-NO-VEGF pathway is present in endothelium from microcirculation and macrocirculation in both normal and pre-eclamptic pregnancies. However, NO signaling pathway seems to be impaired in HUVEC from pre-eclampsia.

• 出版日期2017-3