Activation of the sonic hedgehog signaling controls human pulmonary arterial smooth muscle cell proliferation in response to hypoxia

Guansong Wang, Zhiyuan Zhang, Zhi Xu, Hongjin Yin, Li Bai, Zhuang Ma, Mark A. DeCoster, Guisheng Qian, Guangyu Wu

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

The hedgehog signal pathway plays a crucial role in the angiogenesis and vascular remodeling. However, the function of this pathway in the pulmonary vascular smooth cell proliferation in response to hypoxia remains unknown. In this study, we have demonstrated that the main components of the hedgehog pathway, including sonic hedgehog (SHH), patched1 (PTCH1), smoothened (SMO), GLI and hypoxia-inducible factor 1 (HIF1) are expressed in the human pulmonary arterial smooth muscle cells (HPASMCs). Interestingly, hypoxia significantly enhanced the expression of SHH and HIF1, facilitated the translocation of GLI1 into the nuclei, and promoted the proliferation of HPASMCs. Furthermore, direct activation of the SHH pathway through incubation with the purified recombinant human SHH or with purmorphamine and SAG, two Smo agonists, also enhanced the proliferation of HPASMCs. Importantly, the treatment with anti-SHH and anti-HIF1 antibodies or cyclopamine, a specific SMO inhibitor, markedly inhibited the nuclear translocation of GLI1 and cell proliferation in the HPASMCs induced by hypoxia and activation of the SHH pathway. Moreover, the treatment with cyclopamine increased apoptosis in the hypoxic HPASMCs. These data strongly demonstrate for the first time that the SHH signaling plays a crucial role in the regulation of HPASMC growth in response to hypoxia.

Original languageEnglish (US)
Pages (from-to)1359-1367
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1803
Issue number12
DOIs
StatePublished - Dec 1 2010

Fingerprint

Smooth Muscle Myocytes
Cell Proliferation
Lung
Hypoxia-Inducible Factor 1
Cell Hypoxia
Hypoxia
Blood Vessels
Signal Transduction
Apoptosis
Antibodies
Growth

Keywords

  • Anoxia
  • Cell proliferation
  • GLI
  • Hedgehog signal pathway
  • Human pulmonary arterial smooth muscle cells
  • Sonic hedgehog

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Activation of the sonic hedgehog signaling controls human pulmonary arterial smooth muscle cell proliferation in response to hypoxia. / Wang, Guansong; Zhang, Zhiyuan; Xu, Zhi; Yin, Hongjin; Bai, Li; Ma, Zhuang; DeCoster, Mark A.; Qian, Guisheng; Wu, Guangyu.

In: Biochimica et Biophysica Acta - Molecular Cell Research, Vol. 1803, No. 12, 01.12.2010, p. 1359-1367.

Research output: Contribution to journalArticle

Wang, Guansong ; Zhang, Zhiyuan ; Xu, Zhi ; Yin, Hongjin ; Bai, Li ; Ma, Zhuang ; DeCoster, Mark A. ; Qian, Guisheng ; Wu, Guangyu. / Activation of the sonic hedgehog signaling controls human pulmonary arterial smooth muscle cell proliferation in response to hypoxia. In: Biochimica et Biophysica Acta - Molecular Cell Research. 2010 ; Vol. 1803, No. 12. pp. 1359-1367.
@article{7320a6a0799b42aea3492abbc4c6389b,
title = "Activation of the sonic hedgehog signaling controls human pulmonary arterial smooth muscle cell proliferation in response to hypoxia",
abstract = "The hedgehog signal pathway plays a crucial role in the angiogenesis and vascular remodeling. However, the function of this pathway in the pulmonary vascular smooth cell proliferation in response to hypoxia remains unknown. In this study, we have demonstrated that the main components of the hedgehog pathway, including sonic hedgehog (SHH), patched1 (PTCH1), smoothened (SMO), GLI and hypoxia-inducible factor 1 (HIF1) are expressed in the human pulmonary arterial smooth muscle cells (HPASMCs). Interestingly, hypoxia significantly enhanced the expression of SHH and HIF1, facilitated the translocation of GLI1 into the nuclei, and promoted the proliferation of HPASMCs. Furthermore, direct activation of the SHH pathway through incubation with the purified recombinant human SHH or with purmorphamine and SAG, two Smo agonists, also enhanced the proliferation of HPASMCs. Importantly, the treatment with anti-SHH and anti-HIF1 antibodies or cyclopamine, a specific SMO inhibitor, markedly inhibited the nuclear translocation of GLI1 and cell proliferation in the HPASMCs induced by hypoxia and activation of the SHH pathway. Moreover, the treatment with cyclopamine increased apoptosis in the hypoxic HPASMCs. These data strongly demonstrate for the first time that the SHH signaling plays a crucial role in the regulation of HPASMC growth in response to hypoxia.",
keywords = "Anoxia, Cell proliferation, GLI, Hedgehog signal pathway, Human pulmonary arterial smooth muscle cells, Sonic hedgehog",
author = "Guansong Wang and Zhiyuan Zhang and Zhi Xu and Hongjin Yin and Li Bai and Zhuang Ma and DeCoster, {Mark A.} and Guisheng Qian and Guangyu Wu",
year = "2010",
month = "12",
day = "1",
doi = "10.1016/j.bbamcr.2010.09.002",
language = "English (US)",
volume = "1803",
pages = "1359--1367",
journal = "Biochimica et Biophysica Acta - Molecular Cell Research",
issn = "0167-4889",
publisher = "Elsevier",
number = "12",

}

TY - JOUR

T1 - Activation of the sonic hedgehog signaling controls human pulmonary arterial smooth muscle cell proliferation in response to hypoxia

AU - Wang, Guansong

AU - Zhang, Zhiyuan

AU - Xu, Zhi

AU - Yin, Hongjin

AU - Bai, Li

AU - Ma, Zhuang

AU - DeCoster, Mark A.

AU - Qian, Guisheng

AU - Wu, Guangyu

PY - 2010/12/1

Y1 - 2010/12/1

N2 - The hedgehog signal pathway plays a crucial role in the angiogenesis and vascular remodeling. However, the function of this pathway in the pulmonary vascular smooth cell proliferation in response to hypoxia remains unknown. In this study, we have demonstrated that the main components of the hedgehog pathway, including sonic hedgehog (SHH), patched1 (PTCH1), smoothened (SMO), GLI and hypoxia-inducible factor 1 (HIF1) are expressed in the human pulmonary arterial smooth muscle cells (HPASMCs). Interestingly, hypoxia significantly enhanced the expression of SHH and HIF1, facilitated the translocation of GLI1 into the nuclei, and promoted the proliferation of HPASMCs. Furthermore, direct activation of the SHH pathway through incubation with the purified recombinant human SHH or with purmorphamine and SAG, two Smo agonists, also enhanced the proliferation of HPASMCs. Importantly, the treatment with anti-SHH and anti-HIF1 antibodies or cyclopamine, a specific SMO inhibitor, markedly inhibited the nuclear translocation of GLI1 and cell proliferation in the HPASMCs induced by hypoxia and activation of the SHH pathway. Moreover, the treatment with cyclopamine increased apoptosis in the hypoxic HPASMCs. These data strongly demonstrate for the first time that the SHH signaling plays a crucial role in the regulation of HPASMC growth in response to hypoxia.

AB - The hedgehog signal pathway plays a crucial role in the angiogenesis and vascular remodeling. However, the function of this pathway in the pulmonary vascular smooth cell proliferation in response to hypoxia remains unknown. In this study, we have demonstrated that the main components of the hedgehog pathway, including sonic hedgehog (SHH), patched1 (PTCH1), smoothened (SMO), GLI and hypoxia-inducible factor 1 (HIF1) are expressed in the human pulmonary arterial smooth muscle cells (HPASMCs). Interestingly, hypoxia significantly enhanced the expression of SHH and HIF1, facilitated the translocation of GLI1 into the nuclei, and promoted the proliferation of HPASMCs. Furthermore, direct activation of the SHH pathway through incubation with the purified recombinant human SHH or with purmorphamine and SAG, two Smo agonists, also enhanced the proliferation of HPASMCs. Importantly, the treatment with anti-SHH and anti-HIF1 antibodies or cyclopamine, a specific SMO inhibitor, markedly inhibited the nuclear translocation of GLI1 and cell proliferation in the HPASMCs induced by hypoxia and activation of the SHH pathway. Moreover, the treatment with cyclopamine increased apoptosis in the hypoxic HPASMCs. These data strongly demonstrate for the first time that the SHH signaling plays a crucial role in the regulation of HPASMC growth in response to hypoxia.

KW - Anoxia

KW - Cell proliferation

KW - GLI

KW - Hedgehog signal pathway

KW - Human pulmonary arterial smooth muscle cells

KW - Sonic hedgehog

UR - http://www.scopus.com/inward/record.url?scp=77957784479&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77957784479&partnerID=8YFLogxK

U2 - 10.1016/j.bbamcr.2010.09.002

DO - 10.1016/j.bbamcr.2010.09.002

M3 - Article

VL - 1803

SP - 1359

EP - 1367

JO - Biochimica et Biophysica Acta - Molecular Cell Research

JF - Biochimica et Biophysica Acta - Molecular Cell Research

SN - 0167-4889

IS - 12

ER -