Transcription factor CHF1/Hey2 regulates neointimal formation in vivo and vascular smooth muscle proliferation and migration in vitro

Objective - To determine the role of the cardiovascular-restricted, hairy-related bHLH transcription factor, CHF1/Hey2, in the biological response to vascular injury. Methods and Results - We investigated the response of CHF1/Hey2-deficient mice to vascular injury in vivo and the response of primary cultured vascular smooth muscle cells (VSMCs) from these mice to growth factors in vitro. Neointima formation after arterial wire injury is decreased in knockout ( KO) compared with wild-type (WT) mice (0.025 +/- 0.011 mm(2) in WT [ n = 13]) versus 0.016 +/- 0.008 mm(2) in KO ( n = 12; P < 0.05) and is accompanied by reduced cellular proliferation. CHF1/Hey2-deficient VSMCs proliferate slowly compared with WT VSMCs and also show decreased migration in response to platelet-derived growth factor (PDGF) (62.6 +/- 10.3 CPF versus 37.2 +/- 13.5 CPF; P < 0.01) and heparin-binding epidermal growth factor-like growth factor (HB-EGF) (27.4 +/- 7.7 CPF versus 6.4 +/- 3.7 CPF, P < 0.05). Furthermore, lamellipodia formation and membrane ruffling induced by these chemoattractants are diminished in KO VSMCs, which is correlated with decreased activation of the small GTPase Rac1. Although total Rac1 protein was not changed in KO VSMCs, the level of the Rac guanine exchange factor (GEF), Sos1, was decreased. Conclusions - CHF1/Hey2 is an important regulator of vascular smooth muscle cell (VSMC) accumulation during vascular remodeling and responsiveness to growth factors in vitro.