Potential Role of A_2BAdenosine Receptors on Proliferation/Migration of Fetal Endothelium Derived from Preeclamptic Pregnancies

Abstract

To investigate the functionality of A2B adenosine receptor (A2BAR) and the nitric oxide (NO) and vascular endothelial growth factor (VEGF) signaling pathway in the endothelial cell proliferation/migration during preeclampsia, we used human umbilical vein endothelial cells (HUVECs) isolated from normal pregnancies (n = 15) or pregnancies with preeclampsia (n = 15). Experiments were performed in presence or absence of the nonselective adenosine receptor agonist NECA, the A2BAR selective antagonist MRS-1754, and the nitric oxide synthase (NOS) inhibitor L-NAME. Results indicated that cells from preeclampsia exhibited a significant higher protein level of A2BAR and logEC50 for NECA-mediated proliferation than normotensive pregnancies. The stimulatory effect of NECA (10 μM, 24 h) on cell proliferation was prevented by MRS-1754 (5 nM) coincubation only in cells from normotensive pregnancies. Nevertheless, L-NAME (100 μM, 24 h) reduced the NECA-induced cell proliferation/migration in HUVEC from normal pregnancy; however in preeclampsia only NECA-induced cell proliferation was reduced by L-NAME. Moreover, NECA increased protein nitration and abundance of VEGF in cells from normal pregnancy and effect prevented by MRS-1754 coincubation. Nevertheless, in preeclampsia NECA did not affect the protein level of VEGF. In conclusion HUVECs from preeclampsia exhibit elevated protein level of A2BAR and impairment of A2BAR-mediated NO/VEGF signaling pathway.

Adenosine A2A receptor regulates expression of vascular endothelial growth factor in feto-placental endothelium from normal and late-onset pre-eclamptic pregnancies

“…But, when those cells were incubated in hypoxia (4.6 % oxygen, 1 or 3 h), there was a shift in the expression of A 2B over A 2A , associated with a significant increase in the expression and release of VEGF (eight times) [4]. Although we have not investigated expression of A 2B in this manuscript, previously, we have described high expression of A 2B in HUVEC from LOPE [36]. But contrary to what was found in hypoxia [4], in HUVEC from pre-eclampsia, we did not find an increase in the VEGF protein levels after stimulation with NECA.…”

“…Intracellular pathway involved in A 2 -mediated VEGF expression is not completely elucidated; however, we have found participation of NO in this process [14,36]. Despite the A 2A -NO-VEGF pathway is present in pre-eclamptic pregnancies, participation of NO seems to be associated with gestational age of pre-eclampsia onset.…”

“…However, it has been described that adenosine A 2A (and A 2B ) receptors may increase endothelial proliferation/migration and in vitro angiogenesis capacity, as well as induce vasodilatation, increase the synthesis of proangiogenic factors (i.e., VEGF), or decrease expression of antiangiogenic factors such as sFLT-1 [see details in 1]. In particular, other [2,4,6] and we [14,36] have previously showed that stimulation of A 2A receptor increased the expression of VEGF in endothelial cells, as confirmed in the current work.…”

Letter by Escudero et al Regarding Article, “Elevated Placental Adenosine Signaling Contributes to the Pathogenesis of Preeclampsia”

“…Because we are very interested in this topic, [2][3][4] it is gratifying to see data supporting a role for elevated placental adenosine as a cause rather than an effect of preeclampsia. The authors elegantly dissect mechanisms showing that the ADORA2B receptor is relevant to the demonstrated maternal and fetal changes.…”

“…However, the potential proangiogenic role of adenosine in the placenta via synthesis and release of vascular endothelial growth factor is also present in preeclampsia. 3,4 Therefore characterization of adenosine-mediated placental angiogenesis is needed.…”