Adrenomedullin as an autocrine/paracrine apoptosis survival factor for rat endothelial cells

Adrenomedullin is a potent vasorelaxant/hypotensive peptide recently isolated from human pheochromocytoma. We demonstrate here a novel role of this peptide as an apoptosis survival factor for rat endothelial cells. When rendered quiescent by serum deprivation, a fraction of endothelial cell cultures showed morphological and biochemical features characteristic of apoptosis. Adrenomedullin significantly suppressed apoptosis without inducing cell proliferation. Rat endothelial cells that contained high affinity binding sites for adrenomedullin expressed adrenomedullin gene and released the peptide into culture media. Addition of preimmune rabbit serum prevented apoptosis, whereas rabbit antiadrenomedullin antiserum partially, but significantly, abrogated the protective effect of the preimmune serum, suggesting its autocrine/paracrine role. Although adrenomedullin induced intracellular cAMP formation, other cAMP-elevating agonists, such as prostaglandin I2 and forskolin, did not affect apoptosis. Furthermore, adenosine 3',5'-cyclicmonophosphothioate Rp-isomer, a cAMP antagonist, did not block the cell survival effect of adrenomedullin. Adrenomedullin neither increased intracellular Ca2+ concentrations nor inositol-1,4,5-trisphosphate levels in rat endothelial cells. These results demonstrate that adrenomedullin suppresses serum deprivation-induced apoptosis of rat endothelial cells via cAMP-independent mechanism.