title: Shh mediates PDGF-induced contractile-to-synthetic phenotypic modulation in vascular smooth muscle cells through regulation of KLF4.
abstract: Platelet-derived growth factor (PDGF) is known to induce phenotypic switching of vascular smooth muscle cells (VSMCs) from contractile to a pathological synthetic state, which played an essential role in proliferation of VSMCs. Sonic hedgehog (Shh) contributes to the proliferation of VSMCs when induced by PDGF. Here, we investigated the probable role of Shh in PDGF-induced VSMC dedifferentiation and its underlying mechanisms. We found that PDGF stimulated Shh expression in VSMCs, which was mediated by activation of PDGFRβ/ERK1/2 cell signaling pathway. Further, we found PDGF-induced VSMC phenotypic modulation was accompanied by up-regulation of Shh/Gli family zinc finger 2 (Gli2) signaling and Krüppel-like factor 4 (KLF4). When inhibited Shh in the presence of PDGF, the expressions of KLF4 and VSMC dedifferentiation markers were down-regulated and the effect of PDGF in inducing VSMC dedifferentiation was blocked. In the absence of PDGF, Shh signaling activation increased the expression of KLF4 and promoted VSMC dedifferentiation. The results indicate Shh participated in the regulation of PDGF-induced VSMC dedifferentiation. Finally, we found that KLF4 was closely involved in this process. On inhibition of KLF4, PDGF induced VSMC dedifferentiation was abrogated, even in the presence of Shh. Taken together, the results provide critical insights into the newly discovered role of Shh in phenotypic modulation of VSMCs which depends on KLF4.
authors.affiliation: Department of Vascular Surgery, 1st Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Department of Dermatology, 1st Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wei
authors.affiliation: Department of Vascular Surgery, 1st Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Vascular Surgery, 1st Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors.forename: Xuehu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Vascular Surgery, 1st Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors.forename: Qining
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Department of Vascular Surgery, 1st Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Vascular Surgery, 1st Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. Electronic address: lfh_cmu@126.com.
authors.forename: Fenghe
authors.initials: F
authors.lastname: Li
mesh_terms: D000818:Animals; D054337:Cell Dedifferentiation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D053823:Hedgehog Proteins / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D017208:Rats, Wistar
chemical_list: D053823:Hedgehog Proteins; C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D010982:Platelet-Derived Growth Factor; C546888:Shh protein, rat
keywords: Cell signaling; Kru¨ppel like factor 4; Phenotypic modulation; Sonic hedgehog; Vascular smooth muscle cells