Abstract 319: Novel Therapeutic Mechanism of Placental Growth Factor in Myocardial Infarction: Tissue Repair through Enhancement of Proliferation, Mobilization and Recruitment of BM-Derived Stem Cells for Cardiac Myoangiogenesis
Background: Placental growth factor (PlGF) promotes angiogenesis by activation of VEGFR-1 and stimulates mobilization of hematopoietic stem cells from bone marrow (BM). However, therapeutic effect of PlGF on myocardial angiogenesis and BM stem cell kinetics needs to be further investigated.
Methods and Results: PBS, 500 μg of empty vector (Mock), or plasmid encoding human PlGF (phPlGF) was intramyocardially (i.m.) injected after myocardial infarction (MI) in Sprague Dawley rats. The phPlGF gene transfer resulted in significant preservation of LV function 28 days post MI [(1) +dP/dt: phPlGF, 7046±172; Mock, 5603±147; PBS, 5017±158 mmHg/sec, P<0.01 (2) LVEF: phPlGF, 68.1±2.7; Mock, 34.0±2.0; PBS, 26.3±1.3% P<0.01]. Functional improvement by phPlGF was accompanied with 126% increase in neovascularization, 32% reduction of LV fibrosis, and inhibition of cardiac apoptosis by TUNNEL compared to PBS group (P<0.05). To assess the effect of phPlGF transfer on kinetics of BM-derived stem cells, PBS, Mock, or phPlGF was i.m. injected in nude rats with MI 4 weeks after BM transplantation from GFP transgenic mice. Numbers of BM and peripheral blood (PB) Sca-1+/ lineage− (SL) cells at day 7 were greater in phPlGF group than controls [(1) BM: phPlGF, 51.3±1.8; Mock, 31.4±2.3; PBS, 25.1±1.1%, P<0.01 (2) PB: phPlGF, 364.5±47.3; Mock, 164.3±14.9; PBS, 154.5±12. 6 cells/ μl, P<0.01]. BM-derived stem cells in peri-infarct area at day 7 were more abundantly detected as GFP+/Sca-1+ cells in phPlGF group than controls (phPlGF, 86.5±4.3; Mock, 39.3±1.9; PBS, 26.5±1. 6 cells/mm2, P<0.01). RT-PCR revealed enhanced expression of endogenous VEGF and SDF-1 augmenting recruitment of circulating stem cells. Immunostaining disclosed expression of early cardiomyogenic and vasculogenic markers, GATA4, MEF2C, GATA6 and Ets-1, in the BM-derived stem cells at day 7. In vitro, PlGF protein dose-dependently promotes proliferation and migration of BM-SL cells and enhances the vasculogenic capacity of the BM-SL cells in endothelial colony forming assay.
Conclusion: phPlGF gene transfer may have therapeutic potential for promotion of cardiac myoangiogenesis by augmenting not only local angiogenesis but proliferation, mobilization and recruitment of BM-derived stem cells post MI.