Rationale Vascular smooth muscle cell (VSMC) differentiation from neural crest cells (NCCs) is critical for cardiovascular development, but the mechanisms remain largely unknown. Objective TGF-β function in VSMC differentiation from NCCs is controversial. We therefore determined the role and the mechanism of a TGF-β downstream signaling intermediate Smad2 in NCC differentiation to VSMCs. Methods and Results By using Cre/loxP system, we generated NCC tissue-specific Smad2 knockout mouse model and found that Smad2 deletion resulted in defective NCC differentiation to VSMCs in aortic arch arteries during embryonic development and caused vessel wall abnormality in adult carotid arteries where the VSMCs are derived from NCCs. The abnormalities included missing one layer of VSMCs in the media of the arteries with distorted and thinner elastic lamina, leading to a thinner vessel wall as compared to the wild type vessel. Mechanistically, Smad2 interacted with MRTFB to regulate VSMC marker gene expression. Smad2 was required for TGF-β-induced MRTFB nuclear translocation whereas MRTFB enhanced Smad2 binding to VSMC marker promoter. Moreover, we found that Smad2, but not Smad3, was a progenitor-specific transcription factor mediating TGF-β-induced VSMC differentiation from NCCs. Smad2 appeared to be also involved in determining the physiological differences between NCC- and mesoderm-derived VSMCs. Conclusions Smad2 is an important factor in regulating progenitor-specific VSMC development and physiological differences between NCC- and mesoderm-derived VSMCs.

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