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 ET(A)/
NADPH oxidase pathway in
salt-sensitive
hypertension. Both ET(A) and ET(B) receptors were expressed in EPCs, but only ET(A) 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 ET(A) 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 ET(A) 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 ET(A) antagonist,
NADPH oxidase inhibitor, or
polyethylene glycol-superoxide dismutase. Finally, in ET(B)-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 ET(A)/
NADPH oxidase pathway and diminished
antioxidants critically contribute to
EPC reduction and dysfunction via increased oxidative stress in
salt-sensitive
hypertension.