E2F1 Suppresses Cardiac Neovascularization Via Downregulation Of VEGF And PLGF Expression

Background:The E2F transcription factors are best characterized for their roles in cell-cycle regulation, cell growth, and cell survival. Previously, we have shown that E2F1 is involved in the angiogenic response to ischemic skeletal-muscle injury. Here, we investigated the potential role of E2F1 in cardiac neovascularization.Methods and Results:Myocardial infarction was induced in WT and E2F1—/—mice. Compared to observations in WT mice, cardiac function, capillary density, and endothelial-cell (EC) proliferation were greater (P<0.01), infarct sizes were smaller (P<0.01), apoptotic ECs were less common (P<0.01); border-zone levels of vascular endothelial-cell growth factor (VEGF) (P<0.05) and placental growth factor (PLGF) (P<0.01) were higher; and border-zone p53 levels were lower (P<0.01); in E2F1—/—mice. Blockade of VEGF receptor 2 (VEGFR2) signaling with the selective inhibitor SU5416 or with the VEGFR2-blocking antibody DC101 abolished the differences between E2F1—/—mice and WT mice in cardiac function, infarct size, capillary density, EC proliferation, and EC apoptosis. Hypoxia-induced VEGF and PLGF upregulation was significantly greater in E2F1-/—than in WT cardiac fibroblasts, and E2F1 overexpression suppressed P1GF upregulation both in WT and p53—/—ells; however, VEGF upregulation was suppressed only in WT cells. E2F1 interacted with and stabilized p53 under hypoxic conditions, and both E2F1:p53 binding and the E2F1-induced suppression of VEGF promoter activity were absent in cells that expressed an N-terminally truncated E2F1 mutant.Conclusions:E2F1 limits cardiac neovascularization and functional recovery after MI by suppressing VEGF and PLGF upregulation through p53-dependent and p53—idependent mechanisms, respectively.