Endothelial and smooth muscle cell interaction via FoxM1 signaling mediates vascular remodeling and pulmonary hypertension

Zhiyu Dai, Maggie M. Zhu, Yi Peng, Hua Jin, Narsa Machireddy, Zhijian Qian, Xianming Zhang, You Yang Zhao*

*Corresponding author for this work

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Rationale: Angioproliferative vasculopathy is a hallmark of pulmonary arterial hypertension (PAH). However, little is known about how endothelial cell (EC) and smooth muscle cell (SMC) crosstalk regulates the angioproliferative vascular remodeling. Objectives: To investigate the role of EC and SMC interaction and underlying signaling pathways in pulmonary hypertension (PH) development. Methods: SMC-specific Foxm1 (forkhead box M1) or Cxcr4 knockout mice, EC-specific Foxm1 or Egln1 knockout mice, and EC-specific Egln1/Cxcl12 double knockout mice were used to assess the role of FoxM1 on SMC proliferation and PH. Lung tissues and cells from patients with PAH were used to validate clinical relevance. FoxM1 inhibitor thiostrepton was used in Sugen 5416/hypoxia- and monocrotaline-challenged rats. Measurements and Main Results: FoxM1 expression was markedly upregulated in lungs and pulmonary arterial SMCs of patients with idiopathic PAH and four discrete PH rodent models. Mice with SMC- (but not EC-) specific deletion of Foxm1 were protected from hypoxia- or Sugen 5416/hypoxia-induced PH. The upregulation of FoxM1 in SMCs induced by multiple EC-derived factors (PDGF-B, CXCL12, ET-1, and MIF) mediated SMC proliferation. Genetic deletion of endothelial Cxcl12 in Egln1Tie2Cre mice or loss of its cognate receptor Cxcr4 in SMCs in hypoxia-treated mice inhibited FoxM1 expression, SMC proliferation, and PH. Accordingly, pharmacologic inhibition of FoxM1 inhibited severe PH in both Sugen 5416/hypoxia and monocrotaline-challenged rats. Conclusions: Multiple factors derived from dysfunctional ECs induced FoxM1 expression in SMCs and activated FoxM1-dependent SMC proliferation, which contributes to pulmonary vascular remodeling and PH. Thus, targeting FoxM1 signaling represents a novel strategy for treatment of idiopathic PAH.

Original languageEnglish (US)
Pages (from-to)788-802
Number of pages15
JournalAmerican journal of respiratory and critical care medicine
Volume198
Issue number6
DOIs
StatePublished - Sep 15 2018

Fingerprint

Pulmonary Hypertension
Cell Communication
Smooth Muscle Myocytes
Endothelial Cells
Cell Proliferation
Knockout Mice
Monocrotaline
Lung
Thiostrepton
MSH Release-Inhibiting Hormone
Vascular Remodeling
Rodentia
Up-Regulation
Hypoxia

Keywords

  • CXCL12/CXCR4
  • Endothelial cells
  • Hyperproliferation
  • Pulmonary vascular remodeling
  • Smooth muscle cells

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

@article{6945fac90a1f4611a960b58ce8790480,
title = "Endothelial and smooth muscle cell interaction via FoxM1 signaling mediates vascular remodeling and pulmonary hypertension",
abstract = "Rationale: Angioproliferative vasculopathy is a hallmark of pulmonary arterial hypertension (PAH). However, little is known about how endothelial cell (EC) and smooth muscle cell (SMC) crosstalk regulates the angioproliferative vascular remodeling. Objectives: To investigate the role of EC and SMC interaction and underlying signaling pathways in pulmonary hypertension (PH) development. Methods: SMC-specific Foxm1 (forkhead box M1) or Cxcr4 knockout mice, EC-specific Foxm1 or Egln1 knockout mice, and EC-specific Egln1/Cxcl12 double knockout mice were used to assess the role of FoxM1 on SMC proliferation and PH. Lung tissues and cells from patients with PAH were used to validate clinical relevance. FoxM1 inhibitor thiostrepton was used in Sugen 5416/hypoxia- and monocrotaline-challenged rats. Measurements and Main Results: FoxM1 expression was markedly upregulated in lungs and pulmonary arterial SMCs of patients with idiopathic PAH and four discrete PH rodent models. Mice with SMC- (but not EC-) specific deletion of Foxm1 were protected from hypoxia- or Sugen 5416/hypoxia-induced PH. The upregulation of FoxM1 in SMCs induced by multiple EC-derived factors (PDGF-B, CXCL12, ET-1, and MIF) mediated SMC proliferation. Genetic deletion of endothelial Cxcl12 in Egln1Tie2Cre mice or loss of its cognate receptor Cxcr4 in SMCs in hypoxia-treated mice inhibited FoxM1 expression, SMC proliferation, and PH. Accordingly, pharmacologic inhibition of FoxM1 inhibited severe PH in both Sugen 5416/hypoxia and monocrotaline-challenged rats. Conclusions: Multiple factors derived from dysfunctional ECs induced FoxM1 expression in SMCs and activated FoxM1-dependent SMC proliferation, which contributes to pulmonary vascular remodeling and PH. Thus, targeting FoxM1 signaling represents a novel strategy for treatment of idiopathic PAH.",
keywords = "CXCL12/CXCR4, Endothelial cells, Hyperproliferation, Pulmonary vascular remodeling, Smooth muscle cells",
author = "Zhiyu Dai and Zhu, {Maggie M.} and Yi Peng and Hua Jin and Narsa Machireddy and Zhijian Qian and Xianming Zhang and Zhao, {You Yang}",
year = "2018",
month = "9",
day = "15",
doi = "10.1164/rccm.201709-1835OC",
language = "English (US)",
volume = "198",
pages = "788--802",
journal = "American Journal of Respiratory and Critical Care Medicine",
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publisher = "American Thoracic Society",
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}

Endothelial and smooth muscle cell interaction via FoxM1 signaling mediates vascular remodeling and pulmonary hypertension. / Dai, Zhiyu; Zhu, Maggie M.; Peng, Yi; Jin, Hua; Machireddy, Narsa; Qian, Zhijian; Zhang, Xianming; Zhao, You Yang.

In: American journal of respiratory and critical care medicine, Vol. 198, No. 6, 15.09.2018, p. 788-802.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Endothelial and smooth muscle cell interaction via FoxM1 signaling mediates vascular remodeling and pulmonary hypertension

AU - Dai, Zhiyu

AU - Zhu, Maggie M.

AU - Peng, Yi

AU - Jin, Hua

AU - Machireddy, Narsa

AU - Qian, Zhijian

AU - Zhang, Xianming

AU - Zhao, You Yang

PY - 2018/9/15

Y1 - 2018/9/15

N2 - Rationale: Angioproliferative vasculopathy is a hallmark of pulmonary arterial hypertension (PAH). However, little is known about how endothelial cell (EC) and smooth muscle cell (SMC) crosstalk regulates the angioproliferative vascular remodeling. Objectives: To investigate the role of EC and SMC interaction and underlying signaling pathways in pulmonary hypertension (PH) development. Methods: SMC-specific Foxm1 (forkhead box M1) or Cxcr4 knockout mice, EC-specific Foxm1 or Egln1 knockout mice, and EC-specific Egln1/Cxcl12 double knockout mice were used to assess the role of FoxM1 on SMC proliferation and PH. Lung tissues and cells from patients with PAH were used to validate clinical relevance. FoxM1 inhibitor thiostrepton was used in Sugen 5416/hypoxia- and monocrotaline-challenged rats. Measurements and Main Results: FoxM1 expression was markedly upregulated in lungs and pulmonary arterial SMCs of patients with idiopathic PAH and four discrete PH rodent models. Mice with SMC- (but not EC-) specific deletion of Foxm1 were protected from hypoxia- or Sugen 5416/hypoxia-induced PH. The upregulation of FoxM1 in SMCs induced by multiple EC-derived factors (PDGF-B, CXCL12, ET-1, and MIF) mediated SMC proliferation. Genetic deletion of endothelial Cxcl12 in Egln1Tie2Cre mice or loss of its cognate receptor Cxcr4 in SMCs in hypoxia-treated mice inhibited FoxM1 expression, SMC proliferation, and PH. Accordingly, pharmacologic inhibition of FoxM1 inhibited severe PH in both Sugen 5416/hypoxia and monocrotaline-challenged rats. Conclusions: Multiple factors derived from dysfunctional ECs induced FoxM1 expression in SMCs and activated FoxM1-dependent SMC proliferation, which contributes to pulmonary vascular remodeling and PH. Thus, targeting FoxM1 signaling represents a novel strategy for treatment of idiopathic PAH.

AB - Rationale: Angioproliferative vasculopathy is a hallmark of pulmonary arterial hypertension (PAH). However, little is known about how endothelial cell (EC) and smooth muscle cell (SMC) crosstalk regulates the angioproliferative vascular remodeling. Objectives: To investigate the role of EC and SMC interaction and underlying signaling pathways in pulmonary hypertension (PH) development. Methods: SMC-specific Foxm1 (forkhead box M1) or Cxcr4 knockout mice, EC-specific Foxm1 or Egln1 knockout mice, and EC-specific Egln1/Cxcl12 double knockout mice were used to assess the role of FoxM1 on SMC proliferation and PH. Lung tissues and cells from patients with PAH were used to validate clinical relevance. FoxM1 inhibitor thiostrepton was used in Sugen 5416/hypoxia- and monocrotaline-challenged rats. Measurements and Main Results: FoxM1 expression was markedly upregulated in lungs and pulmonary arterial SMCs of patients with idiopathic PAH and four discrete PH rodent models. Mice with SMC- (but not EC-) specific deletion of Foxm1 were protected from hypoxia- or Sugen 5416/hypoxia-induced PH. The upregulation of FoxM1 in SMCs induced by multiple EC-derived factors (PDGF-B, CXCL12, ET-1, and MIF) mediated SMC proliferation. Genetic deletion of endothelial Cxcl12 in Egln1Tie2Cre mice or loss of its cognate receptor Cxcr4 in SMCs in hypoxia-treated mice inhibited FoxM1 expression, SMC proliferation, and PH. Accordingly, pharmacologic inhibition of FoxM1 inhibited severe PH in both Sugen 5416/hypoxia and monocrotaline-challenged rats. Conclusions: Multiple factors derived from dysfunctional ECs induced FoxM1 expression in SMCs and activated FoxM1-dependent SMC proliferation, which contributes to pulmonary vascular remodeling and PH. Thus, targeting FoxM1 signaling represents a novel strategy for treatment of idiopathic PAH.

KW - CXCL12/CXCR4

KW - Endothelial cells

KW - Hyperproliferation

KW - Pulmonary vascular remodeling

KW - Smooth muscle cells

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