title: Angiotensin II impairs endothelial progenitor cell number and function in vitro and in vivo: implications for vascular regeneration.
abstract: Endothelial progenitor cells (EPCs) contribute to endothelial regeneration. Angiotensin II (Ang II) through Ang II type 1 receptor (AT(1)-R) activation plays an important role in vascular damage. The effect of Ang II on EPCs and the involved molecular mechanisms are incompletely understood. Stimulation with Ang II decreased the number of cultured human early outgrowth EPCs, which express both AT(1)-R and Ang II type 2 receptor, mediated through AT(1)-R activation and induction of oxidative stress. Ang II redox-dependently induced EPC apoptosis through increased apoptosis signal-regulating kinase 1, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase phosphorylation; decreased Bcl-2 and increased Bax expression; and activation of caspase 3 but had no effect on the low cell proliferation. In addition, Ang II impaired colony-forming and migratory capacities of early outgrowth EPCs. Ang II infusion diminished numbers and functional capacities of EPCs in wild-type (WT) but not AT(1)a-R knockout mice (AT(1)a(-/-)). Reendothelialization after focal carotid endothelial injury was decreased during Ang II infusion. Salvage of reendothelialization by intravenous application of spleen-derived progenitor cells into Ang II-treated WT mice was pronounced with AT(1)a(-/-) cells compared with WT cells, and transfusion of Ang II-pretreated WT cells into WT mice without Ang II infusion was associated with less reendothelialization. Transplantation of AT(1)a(-/-) bone marrow reduced atherosclerosis development in cholesterol-fed apolipoprotein E-deficient mice compared with transplantation of apolipoprotein E-deficient or WT bone marrow. Randomized treatment of patients with stable coronary artery disease with the AT(1)-R blocker telmisartan significantly increased the number of circulating CD34/KDR-positive EPCs. Ang II through AT(1)-R activation, oxidative stress, and redox-sensitive apoptosis signal-regulating kinase 1-dependent proapoptotic pathways impairs EPCs in vitro and in vivo, resulting in diminished vascular regeneration.
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Côte-Ste-Catherine Rd, Montréal, Québec H3T 1E2, Canada.
authors.forename: Cathleen
authors.initials: C
authors.lastname: Endtmann
authors.forename: Talin
authors.initials: T
authors.lastname: Ebrahimian
authors.forename: Thomas
authors.initials: T
authors.lastname: Czech
authors.forename: Omar
authors.initials: O
authors.lastname: Arfa
authors.forename: Ulrich
authors.initials: U
authors.lastname: Laufs
authors.forename: Mathias
authors.initials: M
authors.lastname: Fritz
authors.forename: Kerstin
authors.initials: K
authors.lastname: Wassmann
authors.forename: Nikos
authors.initials: N
authors.lastname: Werner
authors.forename: Vasileios
authors.initials: V
authors.lastname: Petoumenos
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
authors.forename: Sven
authors.initials: S
authors.lastname: Wassmann
mesh_terms: D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000627:therapeutic use; D001565:Benzoates / Q000627:therapeutic use; D001808:Blood Vessels / Q000378:metabolism / Q000502:physiology; D016026:Bone Marrow Transplantation / Q000379:methods; D002452:Cell Count; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D004311:Double-Blind Method; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D017257:Ramipril / Q000627:therapeutic use; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D000077333:Telmisartan; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001057:Apolipoproteins E; D001562:Benzimidazoles; D001565:Benzoates; D044140:Receptor, Angiotensin, Type 1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D017257:Ramipril; D000077333:Telmisartan