In this study, we found that PlGF and VEGFR1 expression levels were upregulated in the ischemic myocardium in rats, consistent with previous findings in mice and R428 1037624-75-1 humans. Injection of pPlGF1 in the ischemic myocardium further elevated PlGF levels for period of at least 7 days in vivo. Interestingly, this burst of PlGF secondarily amplified its own expression and induced the expression of several other angiogenic factors. PlGF may have induced the release of such angiogenic signals not only from resident cardiac cells but, perhaps, also from recruited BM-derived progenitors, similar to its effect on angiocompetent BM-derived VEGFR-1 + hemangiocytes, as previously documented. This coordinated joint expression of paracrine angiogenic factors over a period of 7�C 10 days after MI sufficed to stimulate the formation of microvessels as well as of larger conduit vessels for up to at least 28 days after MI. PlGF gene transfer thus stimulated the formation of durable, mature vessels, that failed to regress upon cessation of PlGF gene expression. These findings in the ischemic heart in the rat extend those previous findings in the skin and ischemic limb in mice that showed that PlGF promotes not only the formation of naked endothelial-lined channels but also recruits pericytes and smooth muscle cells around these nascent neovessels, thereby stabilizing them into more mature and regression-resistant vessels. Importantly, this neovasculature was functional, as it improved cardiac performance after PlGF gene therapy. An intriguing but medically relevant finding was that the infarct size was substantially reduced by myocardial PlGF gene therapy. Since the standardized procedure of LAD ligation results in a comparable at-risk ischemic myocardial area, and severely ischemic cardiomyocytes die within 24 to 48 hours, these findings BU 4061T Proteasome inhibitor suggest that PlGF gene transfer preserved cardiomyocyte viability initially via angiogenesis-independent mechanisms. In fact, echocardiography on day 5 revealed that LV functional parameters tended to be slightly better preserved in PlGF group than control groups although the difference was not statistically significant. We cannot exclude the possibility that PlGF gene transfer rescued some of these ischemic myocytes in the periinfarct border regions through vasodilation of residual vessels, but PlGF is a less potent vasodilator than VEGF. Instead, PlGF gene transfer significantly reduced cardiomyocyte apoptosis, presumably through various complementary mechanisms. PlGF is a survival signal for endothelial cells and macrophages, but a similar activity of repairing endangered cardiomyocytes has not as yet been demonstrated. An intriguing question, however, is whether PlGF stimulates cardiomyocyte survival directly or indirectly.