Angiotensin II Impairs Endothelial Progenitor Cell Number and Function In Vitro and In Vivo

Abstract

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 Ϫ/Ϫ). 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 Ϫ/Ϫ 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 Ϫ/Ϫ 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. (Hypertension. 2011;58:394-403.) • Online Data Supplement

Angiotensin II Deteriorates Endothelial Progenitor Cells

“…However, because the angiogenic potential of progenitor cells does not entirely depend on true EPCs, 3 this question seems more academic than of clinical interest. The in vitro results (see Figure 1 of the article by Endtmann et al 4 ) show that non-EPC MNC types are also affected and emphasize the importance of studying the immunomodulatory role of Ang II in vascular disease, a field of research that is gaining attention. In all likelihood, an interplay between EPCs and inflammatory cells exists that is of utmost importance for the vasoprotective effects of pharmacological renin-angiotensin system modulation.…”

“…2,7 The chronic, deleterious effects on cultured EPCs depend on ROS release, and accumulation of damage to macromolecules, in particular to DNA, might be a necessary, timeconsuming interlude between ROS release and induction of apoptosis or senescence. In addition, Endtmann et al 4 observed that ROS production in EPCs is increasing during the first 48 hours of Ang II treatment. Perhaps the induction of deleterious Ang II effects in EPCs requires a high degree of ROS production, for example, to circumvent the protective effect of antioxidant pathways.…”

“…Identification of circulating EPCs should be identified by combining stem cell markers with endothelial cell markers, whereas EPCs obtained from cultured blood, bone marrow, or spleen-derived mononuclear cells (MNCs) should be identified on the basis of endothelial markers and variables of angiogenic function. 2 It is according to these favorable requirements that, in this issue of Hypertension, Endtmann et al 4 show that treatment of adherent, cultured human blood MNCs with angiotensin (Ang) II decreases early outgrowth EPC numbers, colony formation, and migration via Ang II type 1 receptor (AT 1 R) stimulation and that a 12-day infusion of Ang II reduces the numbers of circulating EPCs in wild-type mice. Novel evidence for the involvement of AT 1 Rs in the regulation of vascular repair function of progenitor cells was obtained by studying the effect of wild-type versus AT 1 R Ϫ/Ϫ spleenderived MNCs on neointima formation and re-endothelialization after carotid artery injury in mice.…”

“…Novel evidence for the involvement of AT 1 Rs in the regulation of vascular repair function of progenitor cells was obtained by studying the effect of wild-type versus AT 1 R Ϫ/Ϫ spleenderived MNCs on neointima formation and re-endothelialization after carotid artery injury in mice. Through an elegant series of experiments, Endtmann et al 4 show that AT 1 R signaling inhibits the endothelial repair function of MNCs. In addition, bone marrow replacement studies in apolipoprotein E Ϫ/Ϫ mice suggest that bone marrow AT 1 Rs play a role in atherogenesis.…”

“…Importantly, Endtmann et al 4 show that in vitro Ang II affects EPC numbers through apoptosis, a process mediated by the apoptosis signal-regulating kinase 1-c-Jun N-terminal kinase/p38 mitogen-activated protein kinase-Bax/Bcl2 signaling axis and subsequent caspase 3 activation, and not because of an effect on proliferation. This is a novel finding that complements the observation that Ang II can also decrease EPCs through induction of senescence (Figure).…”