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Ann Thorac Surg 2007;83:646-647
© 2007 The Society of Thoracic Surgeons
Department of Cardiac Surgery, Innsbruck Medical University, Anichstrasse, Innsbruck, 35, 6020 Austria
(Email: nikolaos.bonaros{at}1-med.ac.at; rauend.rauf{at}student.uibk.ac.at; alfred.kocher{at}meduniwien.ac.at).
The role of neoangiogenesis within diseased blood vessels has become one of the outstanding puzzles in the biology of cardiovascular disease. However, in atherosclerosis the role of angiogenesis remains a highly contentious issue, and no consensus exists as to whether angiogenesis is either a key causative factor in the pathogenesis of atherosclerotic plaque formation or whether it is a way to treat coronary artery disease.
Kim and colleagues [1] present the results of a very carefully designed study of vascular endothelial growth factor (VEGF)-based angiogenic therapy using a mixture of myocardial, endothelial, and smooth muscle cells or skeletal myoblasts after myocardial infarction. The authors studied the effect of this therapeutic approach in terms of time, location, and cell type used as a vehicle. They conclude that cell transplantation induced angiogenesis has a durable effect, especially after the use of VEGF-transfected cells. Whether the mechanism of increased efficacy is primarily associated with higher levels of cell engraftment after induction of angiogenesis or with the fact that the transfected cells are able to improve the myocardial environment and subsequently facilitate profuse angiogenesis through paracrine effects remains undetermined. Attempting to answer this question, Celletti and colleagues [2] reported a significant increase in neoangiogenesis and endothelial density 1 week after intraperitoneal administration of recombinant human VEGF-protein in ApoE/ApoB100 deficient mice, whereas an increase in circulating CD34+/Flk1+ endothelial progenitors was not evident until 2 to 3 weeks after VEGF administration. A closer look at the results of the current study indicates that the beneficial effect of VEGF-transfected cells fades 6 months after cell injections, which implies that either injected cells do not survive in ischemic myocardium or they become highly apoptotic and subsequently lose their angiogenic potential. Although the authors have previously shown that the simultaneous expression of both VEGF and IGF-1 transgenes in injected bone marrow cells enhanced the survival and left ventricular function of transplanted cells, the long-term cell survival and apoptotic rates still remain unclear [3]. Although this strategy is supported by an impressive body of pre-clinical research suggesting that VEGF, FGF/2, and other angiogenic cytokines can promote revascularization in diverse animal models of ischemic heart disease, the data from clinical trials have been inconclusive so far. More problematic still for proponents of therapeutic angiogenesis have been several recent studies suggesting that VEGF and other angiogenic factors can promote atherosclerosis in certain animal models and potentially destabilize coronary plaques by promoting intra-lesion angiogenesis [4].
The second major finding of the study is that VEGF overexpression by the transplanted cells does not result in angioma formation even 6 months after cell injections. Other studies indicate that by differential expression of VEGF alone, very different vessel phenotypes including hemangioma-like structures can be obtained [5]. There is now evidence that the phenotypes of neoangiogenesis induced by gene transfer are dictated by the levels or duration of VEGF expression. Although in this study no evidence is provided regarding the phenotypes of newly formed vessels intracardially or extracardially and the levels of VEGF expression of injected cells in vitro, the authors seem to have achieved the correct level of VEGF expression to maximize angiogenesis effect without inducing tumor formation.
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