Journal Article

Endothelial and Smooth Muscle Cell Interaction via FoxM1 Signaling Mediates Vascular Remodeling and Pulmonary Hypertension

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

2018

Overview

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.

• Publisher: Oxford University Press,American Thoracic Society
• Subject: Animals / Cell cycle / Chemokines / Endothelium, Vascular - metabolism / Endothelium, Vascular - physiopathology / Forkhead Box Protein M1 - metabolism / Forkhead Box Protein M1 - physiology / Humans / Hypertension, Pulmonary - metabolism / Hypertension, Pulmonary - pathology / Hypoxia / Lungs / Medical prognosis / Mice / Mice, Knockout / Muscle, Smooth, Vascular - metabolism / Muscle, Smooth, Vascular - physiopathology / Original / Pathogenesis / Pulmonary arteries / Pulmonary hypertension / Signal Transduction / Smooth muscle / Vascular Remodeling