Vascular smooth muscle cells (VSMCs) of the arterial wall play a critical role in the development of occlusive vascular lesions. We demonstrated previously that an absence of cysteine-rich protein 2 (CRP2) enhances VSMC migration and increases neointima formation following arterial injury. Induction of CRP2 by factors present in the injured vessels may serve as a protective mechanism against neointima formation. We recently showed that TGFβ, a key factor present in the injured vessel wall, activates ATF2 phosphorylation and increases CRP2 expression via a CRE element in the Csrp2 (mouse CRP2 gene symbol) gene promoter. Further promoter analysis revealed that a Smad binding element (SBE) immediately 3' to CRE site contributed to CRP2 induction by TGFβ. We then investigated the pathways by which TGFβ induces CRP2 expression in VSMCs. TGFβ not only induced phosphorylation of JNK and ATF2 but also Smad2/3. Interestingly, JNK inhibitor SP600125 abolished TGFβ-induced ATF2 phosphorylation but not that of Smad2/3. In contrast, TGFβ type I receptor inhibitor, SB431542, diminished TGFβ-induced Smad2/3 phosphorylation but not that of JNK or ATF2. These results suggest that two separate pathways converge on Csrp2 promoter to mediate TGFβ induction of CRP2
