ATF4 regulates PI3K/AKT signaling axis to promote angiogenesis after myocardial infarction.

Effective neovascularization is critical for tissue repair and the enhancement of cardiac function following myocardial infarction (MI). However, the hypoxic microenvironment post-MI significantly impedes neovascular formation. Although ATF4 has been implicated in heart failure and myocardial cell regeneration and repair, its role in angiogenesis remains unclear. This study utilized both in vitro and in vivo models to investigate the role of ATF4 in neovascularization after MI. In hypoxia-cultured murine endothelial cells (ECs), hypoxia was observed to inhibit EC proliferation, migration, and tube formation. In contrast, overexpression of ATF4 ameliorated these hypoxia-induced impairments. Conversely, inhibition of ATF4 further exacerbated the reduction in EC proliferation, migration, and tube formation induced by hypoxia. Notably, the beneficial effects of ATF4 were reversed by the PI3K/AKT inhibitor LY294002. Under hypoxic conditions, ATF4 overexpression significantly upregulated phosphorylated (p)-PI3K, p-AKT (T308), and p-AKT (S473) in ECs. LY294002, however, markedly reduced the expression of p-PI3K, p-AKT (T308), and p-AKT (S473) in hypoxic ECs overexpressing ATF4. In a murine MI model, ATF4 overexpression partially mitigated cardiac dysfunction and promoted neovascularization, effects that were significantly attenuated by LY294002. These findings suggest that ATF4 plays a crucial role in endothelial cell-mediated neovascularization under post-MI hypoxia by modulating the PI3K/AKT signaling pathway.