Effects of adrenomedullin on the cell numbers and apoptosis of endothelial progenitor cells

Abstract

Clin Invest Med 2008; 31 (3): E117-E122. AbstractPurpose: To investigate the effect of adrenomedullin on the cell numbers and apoptosis of endothelial progenitor cells (EPCs). Methods: Mononuclear cells were isolated from peripheral blood by Ficoll density gradient centrifugation. The cells were stimulated with adrenomedullin, before and after the treatment of adrenomedullin-receptor antagonist, adrenomedullin 22-52, or a PI3K inhibitor LY294002. Results: Adrenomedullin dose-dependently increased the number of EPCs (P<0.05). Adrenomedullin also significantly decreased apoptosis rate of EPCs in a concentrationdependent manner (P<0.05). In the isolated human mononuclear cells pretreated with adrenomedullin 22-52 or LY294002, adrenomedullin failed to increase the number of EPCs or to reduce the level of apoptosis. Conclusions: Adrenomedullin increases the number of EPCs and decreases their apoptosis. These actions are likely mediated by PI3K signaling pathways. The clinical importance of these favourable effects on EPCs remains to be determined.There is growing evidence that endothelial progenitor cells (EPCs) isolated from peripheral blood are able to travel to the sites of ischemia and endothelial disruption, enhancing endothelial function and neovascularization. 1 A recent study suggests that the level of circulating EPCs predicts the occurrence of cardiovascular events and death from cardiovascular causes and may help to identify patients with increased cardiovascular risk. 2 Augmentation of EPCs with improved functional activity might represent a useful strategy for clinical therapy of coronary artery disease. 3 Adrenomedullin is a potent and long lasing vasodilating peptide, comprising 52 amino acids. It is secreted from endothelial cells, smooth muscle cells and adventitial fibroblasts in various organs, such as the heart, lung, kidney, adipose tissues, and the central nervous system. 4,5 Adrenomedullin signaling is of particular importance in endothelial cell biology, since this peptide protects cells from apoptosis, promotes angiogenesis, and affects vascular tone and permeability. 5 Adrenomedullin has also been shown to enhance the angiogenic potency of bone marrowderived mononuclear cell transplantation, and to improve the cardiac function in rats with myocardial infarction. 6 These beneficial effects are believed to be mediated partly by the angiogenic property of adrenomedullin itself and by its antiapoptotic effect on ORIGINAL RESEARCH

Protective Effect of Adrenomedullin on Rat Leydig Cells from Lipopolysaccharide-Induced Inflammation and Apoptosis via the PI3K/Akt Signaling Pathway ADM on Rat Leydig Cells from Inflammation and Apoptosis

“…Moreover, the protective effect of ADM on LPS-induced damage of Leydig cells was relatively the strongest when ADM was at the concentration of 100 nM. Data from the present study agree with those from previous reports [ 9 , 36 ], although the latter works involved other cell types, such as osteoblasts and endothelial progenitor cells.…”

Adrenomedullin augments the angiogenic potential of late outgrowth endothelial progenitor cells

“…itor and stem cells. These studies have shown that AM suppresses apoptosis and increases the number of early EPCs (23,29). In the present study, we show that these findings also apply to the highly proliferative late EPCs.…”

“…This pathway regulates several important steps in angiogenesis including endothelial cell proliferation, migration, and capillary formation. PI3K/Akt also seem to mediate the antiapoptotic actions of AM on early EPCs (29). While prior studies have demonstrated that AM also induces endothelial cell proliferation and angiogenesis through the activation of MAPK, this was, however, not evident in the EPCs in our study using the MEK1/2 inhibitor U0126 (26).…”

Overexpression of adrenomedullin protects mesenchymal stem cells against hypoxia and serum deprivation‑induced apoptosis via the Akt/GSK3β and Bcl‑2 signaling pathways

“…It has been reported that ADM is not only able to enhance cell proliferation and angiogenesis ( 15 – 17 ), but can inhibit cell apoptosis ( 18 ). Furthermore, it has been demonstrated that ADM protects numerous cell types, including cardiomyocytes ( 19 ), rat Leydig cells ( 20 ), endothelial progenitor cells ( 21 ) and vascular endothelial cells ( 22 ), against apoptosis via the protein kinase B (Akt)/glycogen synthase kinase (GSK)3β signaling pathway. Akt is a powerful survival signal, which suppresses apoptosis and increases cell survival.…”