Vascular endothelial cells regulate vascular tonus, growth, and angiogenesis in response to mechanical stresses. ATP release is one of well-known mechanosensitive responses in endothelial cells. Released ATP induces Ca2+ responses and nitric oxide production in neighboring cells in an auto/paracrine manner. Mechanosensitive and agonist-induced ATP releases are also observed in other cell types, but the cellular mechanisms and pathways of ATP release are largely unknown. Reported candidates for ATP release pathways are ABC proteins including P-glycoprotein and CFTR, exocytosis of ATP-containing vesicles, and ATP-permeable anion channels. In vascular endothelium, vesicular exocytosis, volume-regulated anion channels (VRAC), and connexin hemichannels have been reported as candidates for ATP release pathways. We found that VRAC inhibitors suppressed hypotonic stress-induced ATP release in bovine aortic endothelial cells. Furthermore, extracellular ATP suppressed VRAC current in a voltage dependent manner, which could be fitted to the permeation-blocker model with a Kd (0) of 1 mM and δ value of 0.41. However, it should be noted that VRAC is probably not the only pathway for ATP release in the endothelium, because basal ATP release was not inhibited by VRAC inhibitors. Further investigations are definitely warranted to clarify the details and therapeutic significance of mechanosensitive ATP release in the endothelium.
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