Transcription factor cAMP response element modulator (Crem) restrains Pdgf-dependent proliferation of vascular smooth muscle cells in mice

Seidl M., Steingräber A., Wolf C., Sur T., Hildebrandt I., Witten A., Stoll M., Fischer J., Schmitz W., Müller F.

Abstract

Transcription factors of the cAMP response element-binding protein (Creb)/cAMP response element modulator (Crem) family were linked to the switch from a contractile to a proliferating phenotype in vascular smooth muscle cells (VSMCs). Here, we analyzed the vascular function of Crem in mice with a global inactivation of Crem (Crem−/−). CRE-mediated transcriptional activity was enhanced in primary Crem−/− VSMCs under nonstimulated conditions and under stimulation with Forskolin and platelet-derived growth factor (Pdgf) whereas stimulation with nitric oxide or cGMP showed no effect. This elevated CRE-mediated transcriptional activity as a result of Crem inactivation did not alter aortic contractility or fractions of proliferating or apoptotic aortic VSMCs in situ, and no impact of Crem inactivation on the development of atherosclerotic plaques was observed. Crem−/− mice exhibited an increased neointima formation after carotid ligation associated with an increased proliferation of VSMCs in the carotid media. Pdgf-stimulated proliferation of primary aortic Crem−/− VSMCs was increased along with an upregulation of messenger RNA (mRNA) levels of Pdgf receptor, alpha polypeptide (Pdgfra), cyclophilin A (Ppia), the regulator of G-protein signaling 5 (Rgs5), and Rho GTPase-activating protein 12 (Arhgap12). Taken together, our data reveal the inhibition of Pdgf-stimulated proliferation of VSMCs by repressing the Pdgf-stimulated CRE-mediated transcriptional activation as the predominant function of Crem in mouse vasculature suggesting an important role of Crem in vasculoproliferative diseases.