Targeting Angiotensin-Converting Enzyme-2/Angiotensin-(1-7)/Mas Receptor Axis in the Vascular Progenitor Cells for Cardiovascular Diseases

Abstract

Bone marrow-derived hematopoietic stem/progenitor cells are vasculogenic and play an important role in endothelial health and vascular homeostasis by participating in postnatal vasculogenesis. Progenitor cells are mobilized from bone marrow niches in response to remote ischemic injury and migrate to the areas of damage and stimulate revascularization largely by paracrine activation of angiogenic functions in the peri-ischemic vasculature. This innate vasoprotective mechanism is impaired in certain chronic clinical conditions, which leads to the development of cardiovascular complications. Members of the renin-angiotensin system-angiotensin-converting enzymes (ACEs) ACE and ACE2, angiotensin II (Ang II), Ang-(1-7), and receptors AT1 and Mas-are expressed in vasculogenic progenitor cells derived from humans and rodents. Ang-(1-7), generated by ACE2, is known to produce cardiovascular protective effects by acting on Mas receptor and is considered as a counter-regulatory mechanism to the detrimental effects of Ang II. Evidence has now been accumulating in support of the activation of the ACE2/Ang-(1-7)/Mas receptor pathway by pharmacologic or molecular maneuvers, which stimulates mobilization of progenitor cells from bone marrow, migration to areas of vascular damage, and revascularization of ischemic areas in pathologic conditions. This minireview summarizes recent studies that have enhanced our understanding of the physiology and pharmacology of vasoprotective axis in bone marrow-derived progenitor cells in health and disease. SIGNIFICANCE STATEMENT: Hematopoietic stem progenitor cells (HSPCs) stimulate revascularization of ischemic areas. However, the reparative potential is diminished in certain chronic clinical conditions, leading to the development of cardiovascular diseases. ACE2 and Mas receptor are key members of the alternative axis of the renin-angiotensin system and are expressed in HSPCs. Accumulating evidence points to activation of ACE2 or Mas receptor as a promising approach for restoring the reparative potential, thereby preventing the development of ischemic vascular diseases.

Fig. 1.

Mobilization of hematopoietic progenitor cells (HSPCs) from bone marrow niches. HSPCs are known to reside in two distinct niches: endosteal and vascular niches. HSPCs in the vascular niche are rapidly proliferating and reside in close proximity to the sinusoids; therefore, they are readily available for mobilization into the blood stream in response to physiologic stimuli or pathologic demand. The bone marrow microenvironment contains several cell types, including osteoblasts, mesenchymal stromal cells, endothelial cells, CAR (CXCL12-abundant reticular) cells, fibroblasts, and adipocytes (not all are shown), many of which secrete SDF or vascular VEGF. These two factors indeed help to retain the cells in the bone marrow niches. A shift in the gradient of these factors relative to the concentration in the circulating blood dislodges cells from their niches and transmigrates the sinusoidal wall to peripheral blood. Ischemic tissues stimulate this process by generating SDF and VEGF, which rise to levels severalfold higher than that observed in bone marrow. Mobilized cells home to the areas of ischemia, extravasate into the ischemic tissues, and stimulate vascular regeneration either by trans-differentiation into endothelial cells or by releasing paracrine factors (see text for details).

Fig. 2.

Synthesis and metabolism of angiotensin peptides. Renin secreted from juxtaglomerular cells in the kidney cleaves angiotensinogen in the circulation to angiotensin-(1-10) (Ang I), which is further processed to biologically active peptides, Ang-(1-8) (Ang II) by ACE, Ang-(1-9) by ACE2, and Ang-(1-7) by endopeptidases such as neprilysin (NEP) and prolylendopeptidase (PEP). Ang II is converted by ACE2 or prolylcarboxy peptidase (PCP) to generate Ang-(1-7). Ang II recognizes receptors angiotensin types 1 and 2 receptors (AT1R and AT2R, respectively), whereas Ang-(1-7) interacts with MasR, AT2R, and Mas-related G-protein–coupled receptor member D (MrgD) (Santos et al., 2003; Castro et al., 2005; Tetzner et al., 2016). Ang-(1-9) is known to activate AT2R to produce cardiovascular protective effects (not indicated by arrows) (Ocaranza and Jalil, 2012; Ocaranza et al., 2014). Angiotensin II can be further processed by aminopeptidase A (APA) to form Ang-(2-8), also known as Ang III, which has affinity for both AT1R and AT2R. (Bosnyak et al., 2011) Ang III can be cleaved by alanyl aminopeptidase N (APN) to generate Ang-(3-8), also known as Ang IV, which binds to insulin-regulated membrane aminopeptidase (IRAP), also known as AT4R. (Park et al., 2015) Alternatively, angiotensin II can be processed by aspartate decarboxylase (AD) to produce Ala1-Ang-(1-8), also known as Ang A, which can be converted to Ala1-Ang-(1-7), also known as alamandine, by ACE2. Ang-(1–7) can also be metabolized to alamandine by AD. Alamandine activates MrgD and elicits cardiovascular protective effects. (Lautner et al., 2013)

Fig. 3.

Schematic of protective functions of the ACE2/Ang-(1-7)/MasR pathway in the vasoreparative functions of hematopoietic stem/progenitor cells. ACE2 and MasR are expressed in hematopoietic stem/progenitor cells and vascular endothelium. Activation of either ACE2 to generate Ang-(1-7), or MasR by exogenous Ang-(1-7), stimulates mobilization of HSPCs and angiogenic properties of secretome derived from HSPCs. In the microvascular endothelium, activation of MasR by Ang-(1-7) stimulates angiogenesis (not indicated by arrows) (Hoffmann et al., 2017). Both angiogenic and vasculogenic processes contribute to the vasoreparative functions of Ang-(1-7) (see text for details).