title: Adenosine A2A receptor-dependent proliferation of pulmonary endothelial cells is mediated through calcium mobilization, PI3-kinase and ERK1/2 pathways.
abstract: Hypoxia and HIF-2α-dependent A2A receptor expression and activation increase proliferation of human lung microvascular endothelial cells (HLMVECs). This study was undertaken to investigate the signaling mechanisms that mediate the proliferative effects of A2A receptor. A2A receptor-mediated proliferation of HLMVECs was inhibited by intracellular calcium chelation, and by specific inhibitors of ERK1/2 and PI3-kinase (PI3K). The adenosine A2A receptor agonist CGS21680 caused intracellular calcium mobilization in controls and, to a greater extent, in A2A receptor-overexpressing HLMVECs. Adenoviral-mediated A2A receptor overexpression as well as receptor activation by CGS21680 caused increased PI3K activity and Akt phosphorylation. Cells overexpressing A2A receptor also manifested enhanced ERK1/2 phosphorylation upon CGS21680 treatment. A2A receptor activation also caused enhanced cAMP production. Likewise, treatment with 8Br-cAMP increased PI3K activity. Hence A2A receptor-mediated cAMP production and PI3K and Akt phosphorylation are potential mediators of the A2A-mediated proliferative response of HLMVECs. Cytosolic calcium mobilization and ERK1/2 phosphorylation are other critical effectors of HLMVEC proliferation and growth. These studies underscore the importance of adenosine A2A receptor in activation of survival and proliferative pathways in pulmonary endothelial cells that are mediated through PI3K/Akt and ERK1/2 pathways.
authors.affiliation: Pediatric Airway Research Center, Department of Pediatrics, Aurora, CO 80045, USA. Aftab.Ahmad@UCDenver.edu
authors.forename: Aftab
authors.initials: A
authors.lastname: Ahmad
authors.forename: Jerome B
authors.initials: JB
authors.lastname: Schaack
authors.forename: Carl W
authors.initials: CW
authors.lastname: White
authors.forename: Shama
authors.initials: S
authors.lastname: Ahmad
mesh_terms: D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D049109:Cell Proliferation; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis; D042783:Endothelial Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000166:cytology*; D004789:Enzyme Activation; D006801:Humans; D020935:MAP Kinase Signaling System; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D018047:Receptors, Purinergic P1 / Q000502:physiology*
chemical_list: D018047:Receptors, Purinergic P1; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D002118:Calcium