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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 discoveredmore » role of Shh in phenotypic modulation of VSMCs which depends on KLF4. - Highlights: • Shh as a downstream effector of PDGF participates in PDGF-induced VSMC phenotypic modulation. • Shh can promote VSMC phenotypic switching from contractile to synthetic state. • Shh mediates VSMC phenotypic modulation through regulation of KLF4.« less

Authors:
 [1];  [2]; ; ; ;  [1];  [1]
  1. Department of Vascular Surgery, 1st Affiliated Hospital of Chongqing Medical University, Chongqing 400016 (China)
  2. Department of Dermatology, 1st Affiliated Hospital of Chongqing Medical University, Chongqing 400016 (China)
Publication Date:
OSTI Identifier:
22648588
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 345; Journal Issue: 1; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CELL PROLIFERATION; FINGERS; GROWTH FACTORS; INHIBITION; MODULATION; MUSCLES; PHOSPHOTRANSFERASES; PLANT GROWTH; RECEPTORS; REGULATIONS; SIGNALS; TROPOMYOSIN; ZINC

Citation Formats

Zeng, Qiu, Wei, Bin, Zhao, Yu, Wang, Xuehu, Fu, Qining, Liu, Hong, and Li, Fenghe, E-mail: lfh_cmu@126.com. Shh mediates PDGF-induced contractile-to-synthetic phenotypic modulation in vascular smooth muscle cells through regulation of KLF4. United States: N. p., 2016. Web. doi:10.1016/J.YEXCR.2016.05.014.
Zeng, Qiu, Wei, Bin, Zhao, Yu, Wang, Xuehu, Fu, Qining, Liu, Hong, & Li, Fenghe, E-mail: lfh_cmu@126.com. Shh mediates PDGF-induced contractile-to-synthetic phenotypic modulation in vascular smooth muscle cells through regulation of KLF4. United States. doi:10.1016/J.YEXCR.2016.05.014.
Zeng, Qiu, Wei, Bin, Zhao, Yu, Wang, Xuehu, Fu, Qining, Liu, Hong, and Li, Fenghe, E-mail: lfh_cmu@126.com. Fri . "Shh mediates PDGF-induced contractile-to-synthetic phenotypic modulation in vascular smooth muscle cells through regulation of KLF4". United States. doi:10.1016/J.YEXCR.2016.05.014.
@article{osti_22648588,
title = {Shh mediates PDGF-induced contractile-to-synthetic phenotypic modulation in vascular smooth muscle cells through regulation of KLF4},
author = {Zeng, Qiu and Wei, Bin and Zhao, Yu and Wang, Xuehu and Fu, Qining and Liu, Hong and Li, Fenghe, E-mail: lfh_cmu@126.com},
abstractNote = {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. - Highlights: • Shh as a downstream effector of PDGF participates in PDGF-induced VSMC phenotypic modulation. • Shh can promote VSMC phenotypic switching from contractile to synthetic state. • Shh mediates VSMC phenotypic modulation through regulation of KLF4.},
doi = {10.1016/J.YEXCR.2016.05.014},
journal = {Experimental Cell Research},
number = 1,
volume = 345,
place = {United States},
year = {Fri Jul 01 00:00:00 EDT 2016},
month = {Fri Jul 01 00:00:00 EDT 2016}
}