Endothelin 1 Activation of Endothelin A Receptor/NADPH Oxidase Pathway and Diminished Antioxidants Critically Contribute to Endothelial Progenitor Cell Reduction and Dysfunction in Salt-Sensitive Hypertension

Circulating endothelial progenitor cells (EPCs) are reduced in hypertension, which inversely correlates with its mortality. Deoxycorticosterone acetate (DOCA)-salt hypertension features elevated endothelin (ET) 1 and oxidative stress. We tested the hypothesis that ET-1 induces EPC dysfunction by elevating oxidative stress through the ETA/NADPH oxidase pathway in salt-sensitive hypertension. Both ETA and ETB receptors were expressed in EPCs, but only ETA receptors were significantly increased in EPCs of DOCA-salt rats. EPC number and function were reduced in DOCA-salt rats compared with sham controls, and both were reversed by in vivo blockade of ETA receptors or NADPH oxidase. The enzymatic activities of NAPDH oxidase and its subunits gp91(phox), p22(phox), and Rac1 were augmented in EPCs of DOCA-salt rats, with concomitantly decreased antioxidant enzymes manganese superoxide dismutase, copper-zinc superoxide dismutase, and glutathione peroxidase 1. Reactive oxygen species level was elevated in EPCs from DOCA-salt rats, accompanied by increased EPC telomerase inactivation, senescence, and apoptosis, which were rescued by ETA or NADPH oxidase blockade. Cell therapy of normal or treated DOCA EPCs, but not untreated DOCA EPCs, significantly increased capillary density and blood perfusion in ischemic hindlimbs of DOCA-salt rats. p53 and Bax/Bcl-2 ratios were increased in EPCs of DOCA-salt rats, which were reversed by ETA antagonist, NADPH oxidase inhibitor, or polyethylene glycol-superoxide dismutase, Finally, in ETB-deficient rats, plasma ET-1 was elevated, and EPC number and telomerase activity were diminished. These results demonstrate, for the first time, that both ET-1 activation of ETA/NADPH oxidase pathway and diminished antioxidants critically contribute to EPC reduction and dysfunction via increased oxidative stress in salt-sensitive hypertension. (Hypertension. 2012;59:1037-1043.) circle Online Data Supplement