1 Program for Lung and Vascular Biology, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
2 Division of Critical Care, Department of Pediatrics.
Am J Respir Crit Care Med. 2018 Sep 15;198(6):788-802. doi: 10.1164/rccm.201709-1835OC.
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.
To investigate the role of EC and SMC interaction and underlying signaling pathways in pulmonary hypertension (PH) development.
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.
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 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.
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.
血管增殖性血管病变是肺动脉高压（PAH）的一个标志。然而，内皮细胞（EC）和平滑肌细胞（SMC）相互作用如何调节血管增殖性血管重构的机制尚不清楚。
探讨 EC 和 SMC 相互作用及其潜在信号通路在肺动脉高压（PH）发生发展中的作用。
利用 SMC 特异性 Foxm1（叉头框 M1）或 Cxcr4 敲除小鼠、EC 特异性 Foxm1 或 Egln1 敲除小鼠以及 EC 特异性 Egln1/Cxcl12 双重敲除小鼠来评估 FoxM1 对 SMC 增殖和 PH 的作用。使用来自 PAH 患者的肺组织和细胞来验证临床相关性。在 Sugen 5416/低氧和单克隆抗体- challenged 大鼠中使用 FoxM1 抑制剂 thiostrepton。
特发性 PAH 患者和 4 种不同 PH 啮齿动物模型的肺组织和肺动脉平滑肌细胞中 FoxM1 的表达明显上调。SMC 特异性而非 EC 特异性 Foxm1 缺失的小鼠可免受低氧或 Sugen 5416/低氧诱导的 PH。多种 EC 衍生因子（PDGF-B、CXCL12、ET-1 和 MIF）诱导的 SMC 中 FoxM1 的上调介导 SMC 增殖。Egln1 小鼠内皮细胞 Cxcl12 的基因缺失或低氧处理小鼠中 SMC 中其同源受体 Cxcr4 的缺失抑制 FoxM1 表达、SMC 增殖和 PH。相应地，FoxM1 的药理学抑制可抑制 Sugen 5416/低氧和单克隆抗体- challenged 大鼠的严重 PH。
源自功能失调的 EC 的多种因子诱导 SMC 中 FoxM1 的表达，并激活 FoxM1 依赖性 SMC 增殖，导致肺血管重构和 PH。因此，靶向 FoxM1 信号代表了治疗特发性 PAH 的一种新策略。
