Seidl M D, Steingräber A K, Wolf C T, Sur T M H, Hildebrandt I, Witten A, Stoll M, Fischer J W, Schmitz W, Müller F U
Institute for Pharmacology and Toxicology, University of Münster, Domagkstr. 12, D-48149, Münster, Germany.
Institute for Human Genetics, Genetic Epidemiology, University of Münster, D-48129, Münster, Germany.
Pflugers Arch. 2015 Oct;467(10):2165-77. doi: 10.1007/s00424-014-1652-6. Epub 2014 Nov 27.
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.
环磷酸腺苷反应元件结合蛋白（Creb）/环磷酸腺苷反应元件调节因子（Crem）家族的转录因子与血管平滑肌细胞（VSMCs）从收缩表型向增殖表型的转变有关。在此，我们分析了Crem基因完全失活的小鼠（Crem(-/-)）中Crem的血管功能。在未刺激条件下以及用福斯高林和血小板衍生生长因子（Pdgf）刺激时，原代Crem(-/-)血管平滑肌细胞中CRE介导的转录活性增强，而用一氧化氮或cGMP刺激则无影响。由于Crem失活导致的这种CRE介导的转录活性升高，并未改变主动脉的收缩性或原位增殖或凋亡的主动脉血管平滑肌细胞的比例，且未观察到Crem失活对动脉粥样硬化斑块形成的影响。Crem(-/-)小鼠在颈动脉结扎后内膜增生增加，这与颈动脉中膜血管平滑肌细胞增殖增加有关。原代主动脉Crem(-/-)血管平滑肌细胞在Pdgf刺激下的增殖增加，同时Pdgf受体α多肽（Pdgfra）、亲环蛋白A（Ppia）、G蛋白信号调节因子5（Rgs5）和Rho GTP酶激活蛋白12（Arhgap12）的信使核糖核酸（mRNA）水平上调。综上所述，我们的数据揭示了通过抑制Pdgf刺激的CRE介导的转录激活来抑制Pdgf刺激的血管平滑肌细胞增殖是Crem在小鼠血管系统中的主要功能，这表明Crem在血管增殖性疾病中起重要作用。
