Slug induces a proliferative phenotype of SMC.

<p><b>A,</b> Schematic figure showing the contribution of both Slug and Snail to the phenotypic switch of EC and SMC. Under an inflammatory/hypoxic environment the expression of Slug and Snail increase in EC and promotes EnMT, while only Slug increases in SMC to induce a proliferative SMC phenotype. <b>B,</b> Schematic figure representing the most prominent molecular players involved in the phenotypic switch of SMC. In contractile cells, MYCD-SRF/MRTF-SRF complexes bind to CArG boxes, while bHLH transcription factors, like USF bind to E-boxes to activate and maintain expression of SMC specific markers. In this stage, Slug is minimally expressed. In consequence, expression of its known targets, like CDN1 and KRT19, as well as the tumor suppressor RARRES3, are high and migration is repressed. Expression of the cell cycle related genes, CCNA2 and HBEGF, are highly expressed and the rate of proliferation is very low. Under specific stimuli, such as inflammation and/or hypoxia, the expression of Slug is triggered. Expression of its target genes CDN1 and KRT19 are blocked and cell migration is activated. Moreover, expression of CCNA2 and HBEGF decrease and cells become proliferative. In this condition, the expression of the stem cell factor KLF4 is upregulated. Expression of MYCD and its binding to CArG boxes is also repressed resulting in decreased expression of SMC specific markers. MYCD, myocardin; SRF, serum response factor; MRTF, myocardin-related transcription factors; KLF4, krüppel like factor 4; CDN1, claudin1; KRT19, keratin 19; RARRES3, retinoic acid receptor related gene 3; CCNA2, cyclinA2; HBEGF, Heparin-Binding EGF-Like Growth Factor.