Angiotensin II Deteriorates Endothelial Progenitor Cells

Abstract

A pproximately 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 ϩ 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 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. 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. The in vivo studies do not illuminate whether the AT 1 R-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 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-angioten...

The renin–angiotensin system, bone marrow and progenitor cells

“…In EPCs, this proangiogenic effect depends on NADPH oxidase activation and enhanced VEGF anti-apoptotic function through upregulation of VEGFR2 and improved NO release, as well as on PI3K (phosphoinositide 3-kinase)/Akt signalling [72][73][74]. The deleterious effects of AngII arise from chronic stimulation and consist of two consecutive phases [75]. In the first phase, taking place between days 2 and 5 of stimulation of EPCs with AngII, an AT 1 -receptormediated increase in NADPH oxidase activity leads to ASK-1 (apoptosis signal-regulating kinase-1)/JNK (CJun N-terminal kinase)/p38 MAPK (mitogen-activated protein kinase)/Bax/Bcl2-signalling-induced apoptosis involving caspase 3 [76].…”

“…Employing AT 1 -receptor-KO MNCs and BM transplants in WT and ApoE (apolipoprotein E)-KO mice, it was shown that AT 1 receptor signalling affects vascular repair function and thus promotes atherogenesis [76]. As commented in detail above, it is still unknown whether these in vivo vascular effects solely depend on EPCs or involve an interplay with inflammatory cells or even BM stromal cells [75].…”

Angiotensin II Attenuates the Bioactivities of Human Endothelial Progenitor Cells via Downregulation of β2-Adrenergic Receptor

“…It is known that the effects of Ang II on EPCs are mediated by its interactions with AT1 and AT2 receptors [ 22 ]. Wassmann et al reported that the Ang II-induced detrimental effects originate from AT1R receptor signaling in EPCs [ 23 ].…”

Diverse biological functions of the renin‐angiotensin system

“…128 However, chronic stimulation of this receptor eventually results in a decrease of both EPC levels and functioning. 129,130 Regardless, evidence points to a local RAS being integral to the proliferation, differentiation, and proper function of many cells within the bone marrow, especially when faced with hematopoietic stress.…”