Aims The objective of this study was to investigate whether vascular endothelial growth factor (VEGF) secreted by mesenchymal stem cells (MSC) improves myocardial survival and the engraftment of implanted MSC in infarcted hearts and promotes recruitment of stem cells through paracrine release of myocardial stromal cell-derived factor-1α (SDF-1α).

Methods and results VEGF-expressing MSC (VEGFMSC)-conditioned medium enhanced SDF-1α expression in heart slices and H9C2 cardiomyoblast cells via VEGF and the vascular endothelial growth factor receptor (VEGFR). The VEGFMSC-conditioned medium markedly promoted cardiac stem cell (CSC) migration at least in part via the SDF-1α/CXCR4 pathway and involved binding to VEGFR-1 and VEGFR-3. In vivo , VEGFMSC-stimulated SDF-1α expression in infarcted hearts resulted in massive mobilization and homing of bone marrow stem cells and CSC. Moreover, VEGF-induced SDF-1α guided the exogenously introduced CSC in the atrioventricular groove to migrate to the infarcted area, leading to a reduction in infarct size. Functional studies showed that VEGFMSC transplantation stimulated extensive angiomyogenesis in infarcted hearts as indicated by the expression of cardiac troponin T, CD31, and von Willebrand factor and improved the left ventricular performance, whereas blockade of SDF-1α or its receptor by RNAi or antagonist significantly diminished the beneficial effects of VEGFMSC.

Conclusion Exogenously expressed VEGF promotes myocardial repair at least in part through SDF-1α/CXCR4-mediated recruitment of CSC.

VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart

Despite the enormous progress made in terms of prevention and early intervention, a pressing need remains to develop innovative therapeutic strategies for ischemic cardiovascular disorders, including acute myocardial infarction, chronic cardiac ischemia, peripheral artery disease and stroke. The induction of new blood vessel formation by delivering angiogenic genes to ischemic tissues continues to appear as a promising, alternative strategy to currently available therapies. In aspiring to induce therapeutic angiogenesis, the members of the vascular endothelial growth factor (VEGF) family have long been recognized as major molecular tools. Remarkably, VEGF family members have recently been recognized to also exert multiple, non-angiogenic effects on various cell types, including neurons, skeletal muscle and cardiac cells. Here, we critically review the VEGF-based therapies that have already reached clinical experimentation and highlight the pleiotropic activities of VEGF factors that might create new opportunities for therapeutic application.

VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond.

Mesenchymal Stem Cell-Based Therapy for Cardiovascular Disease: Progress and Challenges

Cell sheet approach for tissue engineering and regenerative medicine.

Heart failure is a devastating condition, the progression of which culminates in a mismatch of oxygen supply and demand, with limited options for treatment. Heart failure has several underlying causes including, but not limited to, ischaemic heart disease, valvular dysfunction, and hypertensive heart disease. Dysfunctional blood vessel formation is a major problem in advanced heart failure, regardless of the aetiology. Vascular endothelial growth factor (VEGF) is the cornerstone cytokine involved in the formation of new vessels. A multitude of investigations, at both the preclinical and clinical levels, have garnered valuable information on the potential utility of targeting VEGF as a treatment option for heart failure. However, clinical trials of VEGF gene therapy in patients with coronary artery disease or peripheral artery disease have not, to date, demonstrated clinical benefit. In this Review, we outline the biological characterization of VEGF, and examine the evidence for its potential therapeutic application, including the novel concept of VEGF as adjuvant therapy to stem cell transplantation, in patients with heart failure.

Anthony Della Siega

Papers

VEGF gene therapy fails to improve perfusion of ischemic myocardium in patients with advanced coronary disease: results of the NORTHERN trial.