Abstract 19423: Angiotensin II Impairs Endothelial Progenitor Cell Number and Function Through Oxidative Stress and Activation of Apoptosis Signal-Regulating Kinase-1: Implications for Vascular Regeneration
Endothelial progenitor cells (EPCs) substantially contribute to endothelial regeneration. Angiotensin II (AngII) through AngII type 1 receptor (AT1-R) plays an important role in vascular damage. The interaction between AngII and EPCs and the involved molecular mechanisms are unclear. Mononuclear cells were isolated from human peripheral blood and cultured on fibronectin. The resulting early outgrowth EPCs were acLDL/lectin double-positive and expressed endothelial cell markers and both AT1-R and AT2-R. Incubation with AngII significantly decreased the number and impaired colony-forming and migratory capacities of EPCs. These effects were associated with AngII-induced increase of oxidative stress. The AngII-mediated reduction of EPC number and function was blocked by AT1-R antagonists and antioxidants (SOD, tiron) but not by AT2-R antagonists. AngII increased EPC apoptosis by two-fold (cleaved caspase III) but had no effect on cell proliferation (Ki67). AngII significantly increased apoptosis signal-regulating kinase-1 (ASK-1), JNK and p38 MAPK phosphorylation, decreased Bcl-2 and increased Bax expression. Pre-incubation of EPCs with SOD abolished AngII-induced activation of cleaved caspase III, ASK-1 and JNK. In vivo, AngII infusion diminished numbers of sca1/flk1-positive EPCs in peripheral blood and reduced the number, colony-forming and migratory capacities of early outgrowth EPCs in wild-type (WT) mice but not in AT1a-R knockout mice (AT1a−/−). Re-endothelialization after focal carotid endothelial injury, which depends in part on functional EPCs, was decreased in AngII- infused WT but not AT1a−/− mice. Salvage of re-endothelialization by intravenous transfusion of spleen-derived progenitor cells into AngII-treated WT mice was significantly pronounced with AT1a−/− cells compared with WT cells. Transfusion of AngII-pretreated WT cells into WT mice without AngII infusion was associated with less re-endothelialization compared with transfusion of vehicle-treated WT or AT1a−/− cells. AngII through AT1-R, oxidative stress and activation of redox-sensitive ASK-1-dependent pro-apoptotic pathways impairs EPC number and function, resulting in profoundly diminished vascular regeneration.
- © 2010 by American Heart Association, Inc.