Editorial Commentary Angiotensin II Deteriorates Endothelial Progenitor Cells Good Intentions With Bad Consequences

Approximately 15 years ago it was discovered that the bone marrow and blood harbor stem cells with angiogenic potential.1 Because some of these stem cells express endothelial markers, it is believed that they are endothelial progenitor cells (EPCs) that will contribute to the maintenance of the circulatory system and develop into adult endothelial cells. Many studies followed to unravel the physiological role and the therapeutic application of EPCs. All of these research endeavors did not yet lead to a consensus regarding the identification of true EPCs, and EPC quantification remains subjective.2 To complicate matters even more, it has now been proposed that nonendothelial CD31 bone marrow cells participate in neovascularization.3 It is, therefore, not only complicated for the investigator to compose a satisfactory study design but also for the reader to evaluate the results. Preferably, such studies investigate circulating, as well as cultured EPCs, and provide proof of their involvement in (patho)physiology through functional studies. 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 al4 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 (AT1R) 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 AT1Rs in the regulation of vascular repair function of progenitor cells was obtained by studying the effect of wild-type versus AT1R / spleenderived MNCs on neointima formation and re-endothelialization after carotid artery injury in mice. Through an elegant series of experiments, Endtmann et al4 show that AT1R signaling inhibits the endothelial repair function of MNCs. In addition, bone marrow replacement studies in apolipoprotein E / mice suggest that bone marrow AT1Rs play a role in atherogenesis. The in vivo studies do not illuminate whether the AT1R-mediated effects are conferred by EPCs, by other MNCs, or bone marrow cell types. 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 al4) 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. Importantly, Endtmann et al4 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).2,5,6 Both processes involve production of reactive oxygen species (ROS) and require several days ( 5 days) of exposure to Ang II. This is in sharp contrast with the antiapoptotic, proangiogenic effect of Ang II on EPCs that was observed in other studies.2,7,8 These stimulatory effects of Ang II takes place on a shorter term ( 5 days). Therefore, the paradoxical findings seem to be based on a temporal difference in exposure to Ang II. Although Ang II-AT1R signaling leads to an immediate angiogenic response, and is meant to operate with good intentions, the chronic activation of this pathway has bad consequences. The putative differential effect on the basis of exposure time can be explained from the distinct manner through which signaling pathways are activated by Ang II in EPCs (Figure of this commentary). The more acute stimulatory effects in cultured EPCs depend on AT1R-mediated facilitation of vascular endothelial growth factor–mediated NO release, involving an increased vascular endothelial growth factor receptor and endothelial NO synthase expression, as well as antiapoptotic phosphatidylinositol 3/Akt signaling.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 The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands. Correspondence to Anton J.M. Roks, Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail [email protected] (Hypertension. 2011;58:356-358.) © 2011 American Heart Association, Inc.