Deletion of Krüppel-like factor 4 in endothelial and hematopoietic cells enhances neointimal formation following vascular injury

Krüppel-like factor 4 (Klf4) is involved in a variety of cellular functions by activating or repressing the transcription of multiple genes.

These results provide evidence that Klf4 in non-SMCs such as ECs regulates neointimal formation by repressing arterial inflammation following vascular injury.

Klf4 conditional knockout (cKO) mice were generated by breeding Tie2-Cre mice and Klf4 floxed mice, and their phenotype was analyzed after carotid ligation injury. Results showed that injury-induced repression of SMC differentiation markers was unaffected by Tie2 promoter-dependent Klf4 deletion. However, of interest, neointimal formation was significantly enhanced in Klf4-cKO mice 21 days following carotid injury. Moreover, Klf4-cKO mice exhibited an augmented proliferation rate, enhanced accumulation of macrophages and T lymphocytes, and elevated expression of cell adhesion molecules including vascular cell adhesion molecule-1 (Vcam1) and E-selectin in injured arteries. Mechanistic analyses in cultured ECs revealed that Klf4 inhibited tumor necrosis factor-α-induced expression of Vcam1 through blocking the binding of nuclear factor-κB to the Vcam1 promoter. Conclusions: These results provide evidence that Klf4 in non-SMCs such as ECs regulates neointimal formation by repressing arterial inflammation following vascular injury.