Objective-This study was performed to evaluate the angiogenic effect of implantation of peripheral blood mononuclear cells (PB-MNCs) compared with bone marrow mononuclear cells (BM-MNCs) into ischemic hibernating myocardium. Methods and Results-A NOGA electromechanical system was used to map the hibernating region and to inject cells.PB-MNCs and BM-MNCs contained similar levels of vascular endothelial growth factor and basic fibroblast growth factor, whereas contents of angiogenic cytokines (interleukin-1 and tumor necrosis factor-␣) were larger in PB-MNCs. Numbers of endothelial progenitors were Ϸ500-fold higher in BM-MNCs. In BM-MNC-implanted myocardia of pigs, an increase in systolic function (ejection fraction from 33% to 52%) and regional blood flow (2.1-fold) and a reduction of the ischemic area (from 29% to 8%) were observed. PB-MNC implantation reduced the ischemic area (from 31% to 17%), the extent of which was less than that seen with BM-MNCs. In saline-implanted myocardium, the ischemic area expanded (from 28% to 38%), and systolic function deteriorated. Angiography revealed an increase in collateral vessel formation by PB-MNC or BM-MNC implantation. Capillary numbers were increased 2.6-and 1.7-fold by BM-MNC and PB-MNC implantation, respectively. BM-MNCs but not PB-MNCs were incorporated into neocapillaries. Conclusions-Catheter-based implantation of PB-MNCs can effectively improve collateral perfusion and regional function in hibernating ischemic myocardium by its ability to mainly supply angiogenic factors and cytokines. T herapeutic angiogenesis is a new and promising strategy to revascularize ischemic myocardium by stimulation of the growth of new blood vessels or maturation of preexisting collaterals. 1 Angiogenesis is induced by surgical or catheterbased delivery of angiogenic molecules, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). 2,3 Double-blind placebo-controlled clinical studies have indicated that intracoronary infusion of VEGF 4 or FGF2 5 does not improve myocardial perfusion, whereas catheter-based gene transfer of VEGF produces an increase in regional perfusion in patients with ischemic myocardium. 6 Myogenic cell grafting into the damaged myocardium is a promising approach for the treatment of heart failure. We and others have shown previously that intramyocardial transplantation of bone marrow (BM) mononuclear cells (MNCs) improves regional perfusion and systolic function in animal models of ischemic heart failure. [7][8][9][10] Marked increase in cardiac function after BM-MNC implantation may be due not only to neovascularization but also to cardiomyogenesis derived from marrow hematopoietic cells (see review 11 ) and/or marrow mesenchymal cells. 12 Hamano et al 13 reported the clinical efficacy and safety of BM-MNC implantation in 5 patients with ischemic heart disease in combination with bypass surgery. Thus, BM-MNC implantation may be feasible to salvage myocardial ischemia, although this procedure requires a minithoracotomy to exp...
Abstract-It remains undetermined whether continuous endothelial nitric oxide (NO) overexpression exerts angiogenic action. We surgically induced hindlimb ischemia in transgenic mice overexpressing endothelial NO synthase in the endothelium (eNOS-Tg) and studied neocapillary formation, ischemia-induced vascular endothelial growth factor (VEGF) expression, cGMP accumulation, and Akt/PKB signaling. Laser Doppler imaging revealed a markedly increased recovery of blood perfusion in ischemic limbs of eNOS-Tg mice (44% increase) compared with that in wild-type mice. Angiography showed a marked increase in basal and ischemia-induced collateral vessel formation in eNOS-Tg mice. Basal capillary densities and tissue cGMP levels were increased in eNOS-Tg mice (1.8-fold and 1.6-fold versus wild-type mice, respectively). Ischemia-induced neocapillary formation and cGMP accumulation were markedly increased in eNOS-Tg mice (3.6-fold and 4.1-fold versus preischemia levels, respectively), whereas those in wild-type mice were much less (1.8-fold and 1.5-fold, respectively). Basal and time-dependent VEGF expression in ischemic muscles did not differ between eNOS-Tg and wild-type mice. Basal and VEGF-mediated Akt phosphorylation in aortas was similar between eNOS-Tg and wild-type mice. Aortic basal eNOS expression was increased 3.3-fold, and VEGF-mediated eNOS phosphorylation was markedly induced in aortas of eNOS-Tg compared with preischemia levels (4.2-fold), whereas much smaller changes were observed in wild-type mice (1.8-fold increase). Our study demonstrates that overexpression of eNOS protein causes a marked increase in neocapillary formation in response to tissue ischemia without affecting ischemia-induced VEGF expression or VEGF-mediated Akt phosphorylation.
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