Abstract
Insufficient neovascularization, characterized by poor endothelial cell (EC) growth, contributes to the pathogenesis of ischemic heart disease and limits cardiac tissue preservation and regeneration. The E2F family of transcription factors are critical regulators of the genes responsible for cell-cycle progression and growth; however, the specific roles of individual E2Fs in ECs are not well understood. Here we investigated the roles of E2F2 and E2F3 in EC growth, angiogenesis, and their functional impact on myocardial infarction (MI). An endothelial-specific E2F3-deficient mouse strain VE-Cre; E2F3fl/fl was generated, and MI was surgically induced in VE-Cre; E2F3fl/fl and E2F2-null (E2F2 KO) mice and their wild-type (WT) littermates, VE-Cre; E2F3+/+ and E2F2 WT, respectively. The cardiac function, infarct size, and vascular density were significantly better in E2F2 KO mice and significantly worse in VE-Cre; E2F3fl/fl mice than in their WT littermates. The loss of E2F2 expression was associated with an increase in the proliferation of ECs both in vivo and in vitro, while the loss of E2F3 expression led to declines in EC proliferation. Thus, E2F3 promotes while E2F2 suppresses ischemic cardiac repair through corresponding changes in EC proliferation; and differential targeting of specific E2F members may provide a novel strategy for therapeutic angiogenesis of ischemic heart disease.
Highlights
Ischemic heart disease (IHD) represents one of the largest epidemics facing the aging population
VE-Cre; E2F3fl/fl exhibited a worsened heart function as compared with VE-Cre; E2F3+/+ mice at days 14 and 28 post-myocardial infarction (MI) (Figure 1). These results suggest that E2F3 improved while E2F2 impairs cardiac function in response to ischemic injury
Here we found that endothelial cell (EC) growth, neovascularization, and cardiac function post-MI are improved by the loss of E2F2 expression and impaired by the loss of endothelial E2F3 expression, which suggest that E2F2 and E2F3 play contrasting roles
Summary
Ischemic heart disease (IHD) represents one of the largest epidemics facing the aging population. Insufficient neovascularization, characterized by poor vessel growth and survival, contributes to the pathogenesis of IHD and limits cardiac tissue preservation and regeneration; enhancement of cardiac neovascularization is a therapeutic goal. Vascular injury recruits endothelial cells (ECs) required for neovascularization to restore blood perfusion [1,2,3,4,5]. Accumulating evidence indicates that neovascularization is critically dependent on the appropriate regulation of EC cell cycle [11,12]; a deficient endothelial proliferative response to ischemia can result in tissues necrosis [13]. ECs can contribute to cardiac repair by mediating favorable cell:cell interactions and secreting paracrine factors that protect the function and survival of cardiomyocytes [14]
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