Statin and Stromal Cell-Derived Factor-1 Additively Promote Angiogenesis by Enhancement of Progenitor Cells Incorporation into New Vessels

Abstract

Angiogenesis requires the mobilization of progenitor cells from the bone marrow and homing of progenitor cells to ischemic tissue. Statins facilitate the former, and the chemokine stromal cell-derived factor-1 (SDF-1) enhances the latter. Their combined influence on angiogenesis was studied in vivo in the ischemic hindlimb C57BL/6 mouse model. The ischemic to non-ischemic perfusion ratio increased from 0.29 ؎ 0.02 immediately after femoral excision to 0.51 ؎ 0.10 three weeks after the surgery in the mice treated with either fluvastatin or SDF-1 alone, which is significantly better than the control (0.38 ؎ 0.05, p < .05, n ‫؍‬ 6). The combined use of fluvastatin and SDF-1 further improved the reperfusion ratio (0.62 ؎ 0.08, p < .05). More cell proliferation, less apoptosis, enhanced bone marrow-derived endothelial progenitor cell (EPC) incorporation and higher capillary density were observed in ischemic tissue treated with both statin and SDF-1. In vitro monotreatment with either fluvastatin (100 nM) or SDF-1 (100 ng/ ml) facilitated EPC proliferation and migration, inhibited EPC apoptosis, enhanced expression of matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9), and increased Akt phosphorylation and nitric oxide production. These effects were significantly augmented by the two agents together and ablated by inhibitors of either Akt or nitric oxide synthase (NOS). In conclusion, statin and SDF-1 additively enhance progenitor cell migration and proliferation and down-regulate EPC apoptosis, resulting in improved reperfusion via activation of the Akt/NOS pathway and up-regulation of MMP-2 and MMP-9 expression.

Effect of Locally Applied Fluvastatin in Low-turnover Osteoporosis Model Mouse with Femur Bone Defect

“…Statins are competitive inhibitors of 3-hydroxy-2-methylglutaryl coenzyme A (HMG-CoA) reductase, and are widely used to lower cholesterol levels, which is an important factor in the treatment of hyperlipidemia and arteriosclerosis 4) . Recently, another in vivo effect of statins has also attracted attention, with a number of studies finding that statins promote the differentiation of osteoblasts produced by stimulation with bone morphogenetic protein-2 (BMP-2), indicating their potential in the development of new osteogenic drugs [5][6][7][8] .…”

Cell-based cardiovascular repair and regeneration in acute myocardial infarction and chronic ischemic cardiomyopathy current status and future developments

“…Pretreatment of endothelial progenitor cells with statins, eNOSoverexpression of PPAR-gamma agonists before transfer increases their migratory, invasive, and neovascularization capacity -effects that are mediated by activation of endothelial nitric oxide synthase (Shao et al 2008;Spyridopoulos et al 2004). Similary, own results showed that prestimulation of endothelial progenitor cells from diabetic individuals with the peroxisome proliferator activated receptor -agonist rosiglitazone, enhances nitric oxide availability and the in vivo endothelial repair capacity of these cells (Sorrentino et al 2007).…”

The potential of statin and stromal cell-derived factor-1 to promote angiogenesis

“…[4][5][6] Statins have also been reported to enhance EPC migration, augment EPC chemotaxis and inhibit EPC apoptosis both in vitro and in vivo. 4,9,10 SDF-1, an 89-amino acid polypeptide, is a member of the chemokine CXC subfamily originally isolated from murine bone marrow stromal cells. 11 SDF-1 was initially identified as a potent chemoattractant for lymphocytes and monocytes, and as an enhancer of B cell proliferation.…”

“…16,17 Furthermore, SDF-1 also reduces EPC apoptosis and enhances survival of the progenitor cells. 3,18 SDF-1, either delivered locally in its protein form, 3,19,20 or generated in situ via plasmid and viral vector-mediated gene expression, 10,21,22 enhances neovascularization by augmenting EPC recruitment into ischemic tissues. The potential of statin and stromal cell-derived factor-1 to promote angiogenesis SDF-1 binding to its receptor CXCR4 on the cell surface provides essential signals for mobilization and homing of EPCs to the injured site.…”

“…30 To explore if the combined use of a statin to mobilize BM EPCs and local overexpression of SDF-1 to augment EPC homing to ischemic muscle will result in superior angiogenesis versus use of either agent alone, we used the murine hindlimb ischemia model to determine the effects of Fluvastatin and SDF-1 on angiogenesis. 10 Fluvastatin (5 mg/kg) was injected intra-peritoneally into the mice daily for 7 days to mobilize progenitor cells prior to ischemiainducing surgery. NIH 3T3 cells transduced with the retroviral vector carrying SDF-1 gene were injected I.M.…”