Endothelial and Smooth Muscle Cell Interaction via FoxM1 Signaling Mediates Vascular Remodeling and Pulmonary Hypertension
Endothelial and Smooth Muscle Cell Interaction via FoxM1 Signaling Mediates Vascular Remodeling and Pulmonary Hypertension
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DOI：
10.1164/rccm.201709-1835oc
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发表时间：
2018-09-15
影响因子：
24.7
通讯作者：
Zhao, You-Yang
中科院分区：
文献类型：
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作者：
Dai, Zhiyu;Zhu, Maggie M.;Zhao, You-Yang
依据：血管增生性血管病变是肺动脉高压（PAH）的标志。目的：探讨内皮细胞（EC）和平滑肌细胞（SMC）相互作用及其信号通路在肺动脉高压（PH）发生发展中的作用。SMC特异性Foxm 1（叉头框M1）或Cxcr 4敲除小鼠，EC特异性Foxm 1或Egln 1敲除小鼠，和EC特异性Egln 1/Cxcl 12双敲除小鼠用于评估FoxM 1对SMC增殖和PH的作用。肺组织和PAH患者的细胞用于验证临床相关性。FoxM 1抑制剂硫链丝菌素被用于Sugen 5416/缺氧和野百合碱攻击rats. Measures和主要结果：FoxM 1的表达显着上调肺和肺动脉平滑肌细胞的特发性肺动脉高压和四个离散PH啮齿动物模型的患者。SMC特异性缺失Foxm 1（EC特异性缺失Foxm 1）的小鼠对缺氧或Sugen 5416/缺氧诱导的PH具有保护作用。多种EC衍生因子（PDGF-B、CXCL 12、ET-1和MIF）诱导的SMC中Foxm 1的上调介导SMC增殖。Egln 1（Tie 2Cre）小鼠中内皮细胞Cxcl 12的遗传缺失或缺氧处理小鼠中SMC中其同源受体Cxcr 4的缺失抑制FoxM 1表达、SMC增殖和PH。因此，FoxM 1的药理学抑制抑制了Sugen 5416/缺氧和野百合碱攻击大鼠中的严重PH。来自功能失调的EC的多种因子诱导SMC中FoxM 1的表达并激活FoxM 1依赖性SMC增殖，这有助于肺血管重塑和PH。靶向FoxM 1信号转导代表了治疗特发性PAH的新策略。
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 Egln1(Tie2Cre) 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.