Role of the renin angiotensin system on bone marrow-derived stem cell function and its impact on skeletal muscle angiogenesis

Abstract

Autologous bone marrow cell (BMC) transplantation has been shown as a potential approach to treat various ischemic diseases. However, under many conditions BMC dysfunction has been reported, leading to poor cell engraftment and a failure of tissue revascularization. We have previously shown that skeletal muscle angiogenesis induced by electrical stimulation (ES) is impaired in the SS/Mcwi rats and that this effect is related to a dysregulation of the renin angiotensin system (RAS) that is normalized by the replacement of chromosome 13 derived from the Brown Norway rat (SS-13(BN)/Mcwi consomic rats). The present study explored bone marrow-derived endothelial cell (BM-EC) function in the SS/Mcwi rat and its impact on skeletal muscle angiogenesis induced by ES. SS/Mcwi rats were randomized to receive BMC from: SS/Mcwi; SS-13(BN)/Mcwi; SS/Mcwi rats infused with saline or ANG II (3 ng kg(-1) min(-1)). BMC were injected in the stimulated tibialis anterior muscle of SS/Mcwi rats. Vessel density was evaluated in unstimulated and stimulated muscles after 7 days of ES. BMC isolated from SS/Mcwi or SS/Mcwi rats infused with saline failed to restore angiogenesis induced by ES. However, BMC isolated from SS-13(BN)/Mcwi and SS/Mcwi rats infused with ANG II effectively restored the angiogenesis response in the SS/Mcwi recipient. Furthermore, ANG II infusion increased the capacity of BM-EC to induce endothelial cell tube formation in vitro and slightly increased VEGF protein expression. This study suggests that dysregulation of the RAS in the SS/Mcwi rat contributes to impaired BM-EC function and could impact the angiogenic therapeutic potential of BMC.

Angiotensin-converting enzyme (ACE) genotypes and disability in hospitalized older patients

“…However, data indicating an association between the ACE I/D polymorphism and functional decline or physical performance in older adults are still under debate (Frederiksen et al 2003a, b;Kritchevsky et al 2005;Giaccaglia et al 2008;Yoshihara et al 2009). Indeed, the mechanisms for the interesting findings on muscle performance and endurance remain unclear although some hypotheses have been suggested to include altered substrate delivery in subjects as a result of modulated cardiac output and muscle vascularisation (Montgomery et al 1998), both of which ACE could mediate as a result of its role in the formation of the angiogenic and vasoactive angiotensin II peptide (de Resende et al 2010). In the present study, we investigated the potential association between the ACE I/D polymorphism and the activities of daily living (ADL) in hospitalized older patients.…”

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

“…VEGF-A induces neovascularization and may be a valuable type of therapy for the treatment of peripheral vascular disease (22). During physiological angiogenesis, an increase in VEGF expression stimulates endothelial cell (EC) tube formation and increased microvessel density (3,16,39). Hypoxia is known to produce an angiogenic response, and heightened levels of VEGF-A have been seen in oxygendeprived epithelial, endothelial, and bone marrow cells (13,16,40,51,57).…”

“…During physiological angiogenesis, an increase in VEGF expression stimulates endothelial cell (EC) tube formation and increased microvessel density (3,16,39). Hypoxia is known to produce an angiogenic response, and heightened levels of VEGF-A have been seen in oxygendeprived epithelial, endothelial, and bone marrow cells (13,16,40,51,57). Hypoxic conditions increase levels of hypoxiainducible factor 1␣ (HIF-1␣), which in turn upregulates VEGF-A expression by binding to a hypoxia response element (51,57,61).…”

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

“…Concomitant percutaneous trans-luminal renal angioplasty with MSC therapy has been reported to decrease inlammation, ibrinogenesis and vascular remodelling in atherosclerotic renal artery stenosis of swine [15]. Also, MSCs have the ability to recognize inlammation lesions, and Ang II efects the migration and homing of these cells to the site of injury [16]. Dysregulation of the RAS decreases the paracrine therapeutic potential of MSCs [17].…”

“…Also, MSCs have the ability to recognize inlammation lesions, and Ang II efects the migration and homing of these cells to the site of injury [16]. Dysregulation of the RAS decreases the paracrine therapeutic potential of MSCs [17].…”