The renin–angiotensin system, bone marrow and progenitor cells

Abstract

<jats:p>Modulation of the RAS (renin–angiotensin system), in particular of the function of the hormones AngII (angiotensin II) and Ang-(1–7) [angiotensin-(1–7)], is an important target for pharmacotherapy in the cardiovascular system. In the classical view, such modulation affects cardiovascular cells to decrease hypertrophy, fibrosis and endothelial dysfunction, and improves diuresis. In this view, excessive stimulation of AT1 receptors (AngII type 1 receptors) fulfils a detrimental role, as it promotes cardiovascular pathogenesis, and this is opposed by stimulation of the AT2 receptor (angiotensin II type 2 receptor) and the Ang-(1–7) receptor encoded by the Mas proto-oncogene. In recent years, this view has been broadened with the observation that the RAS regulates bone marrow stromal cells and stem cells, thus involving haematopoiesis and tissue regeneration by progenitor cells. This change of paradigm has enlarged the field of perspectives for therapeutic application of existing as well as newly developed medicines that alter angiotensin signalling, which now stretches beyond cardiovascular therapy. In the present article, we review the role of AngII and Ang-(1–7) and their respective receptors in haematopoietic and mesenchymal stem cells, and discuss possible pharmacotherapeutical implications.</jats:p>

Local hematopoietic renin-angiotensin system in myeloid versus lymphoid hematological neoplastic disorders

“…Mas receptors present in the BM microenvironment mediate the proliferative effect of Ang 1-7 on HSCs. 35 Deficiency of ACE2 in BM-derived cells increased mRNA abundance of a macrophage marker (F4/80) and tumor necrosis factor-alpha (TNF-α) in the stromal vascular fraction of retroperitoneal adipose tissue, suggesting increased infiltration of macrophages into adipose tissue of chimeric mice lacking ACE2 in leukocytes. 36 In our study, ACE1 and ACE2 expressions were found to be significantly higher in the myeloid neoplastic disorders when compared to the lymphoid cancers.…”

Vascular endothelial growth factor-A signaling in bone marrow-derived endothelial progenitor cells exposed to hypoxic stress

“…Recruitment of BM-EPCs to the vascular lumen occurs after induction of cardiovascular stress (18), although the exact mechanism by which this occurs is not known. BM-EPCs are classified as early stage (2 days to 3 wk in culture after isolation from the bone marrow) at which point they resemble angiogenic monocytes or macrophages with low proliferation and capacity for enhancing tube formation or late stage (3)(4)(5)(6)(7)(8)(9)(10)(11)(12) wk in culture after isolation from the bone marrow) with a highly proliferative nature and ability to form tubes (18,54,55,59). However, BM-EPC identity and characterization are nontrivial and debated in the field (20).…”

“…Since the proper markers to use for BM-EPCs are highly debated, it is very important to denote specific growth conditions, markers, and phenotypic characterizations used when classifying BM-EPCs. One hallmark of the CD34ϩ/VEGFR-2ϩ population of BM-EPCs is that they have been associated with coronary artery disease (7,18,62). Once in the vasculature, the relationship of this population of BMEPCs to neovascularization has been linked to enhanced antiapoptotic function through VEGF-A stimulation of VEGFR-2, increased nitric oxide (NO) release, and enhanced PI3K/AKT signaling (18,32,68).…”

“…Bone marrow-derived endothelial progenitor cells (BMEPCs) are specific progenitor cells from a hematopoietic cell lineage found in the bone marrow that have the ability to develop endothelial-like features and are implicated in endothelial repair, angiogenesis, and vasculogenesis when stimulated by potent proangiogenic factors (4,18,53,55,59). Recruitment of BM-EPCs to the vascular lumen occurs after induction of cardiovascular stress (18), although the exact mechanism by which this occurs is not known.…”

Current Research of the Renin-Angiotensin System Effect on Stem Cell Therapy

“…The other possible mechanism is proposed to be the involvement of JAK (Janus kinase)/STAT (signal transducer and activator of transcription) pathway. JAK/STAT pathway is known to be activated by Ang II [40].…”