Pulmonary and Critical Care Medicine Division, and Victoria Johnson Center for Pulmonary Ocbstructive Research, Virginia Commonwealth University, Richmond, VA, USA.
Eur Respir J. 2013 Jan;41(1):104-14. doi: 10.1183/09031936.00196511. Epub 2012 Jul 26.
Epidemiological evidence links pulmonary arterial hypertension (PAH) with thyroid disease, but a mechanistic explanation for this association is lacking. Because a central hallmark of vascular remodelling in pulmonary hypertension is lumen obliteration by endothelial cell growth and because thyroid hormones are known to be angiogenic, we hypothesised that thyroid hormones play a role in the control of endothelial cell proliferation in experimental PAH in rats. Hypothyroidism was induced by subtotal thyroidectomy and treatment with propylthiouracil (PTU) in rats with experimental PAH after combined exposure to vascular endothelial growth factor receptor inhibition and hypoxia (the Sugen-chronic hypoxia (SuHx) model). Subtotal thyroidectomy prevented and PTU treatment reversed the development of severe experimental PAH. Thyroxin repletion restored the PAH phenotype in thyroidectomised SuHx rats. The prevention of PAH by thyroidectomy was associated with a reduced rate of cell turnover, reduced extracellular signal-regulated protein kinases 1 and 2 phosphorylation, and reduced expression of α(v)β(3) integrin, fibroblast growth factor (FGF)-2 and FGF receptor. Thyroidectomy mitigated hypoxia-induced pulmonary hypertension, but this effect was not associated with a decreased pulmonary vascular resistance. These data suggest that thyroid hormone permits endothelial cell proliferation in PAH. A causal link between thyroid diseases and the onset or progression of vascular remodelling in PAH patients remains to be determined.
流行病学证据将肺动脉高压（PAH）与甲状腺疾病联系起来，但这种关联的机制解释尚缺乏。由于血管重构的一个中心标志是血管内皮细胞生长导致管腔闭塞，并且已知甲状腺激素具有血管生成作用，我们假设甲状腺激素在大鼠实验性 PAH 中内皮细胞增殖的控制中发挥作用。甲状腺功能减退症通过甲状腺次全切除术和丙硫氧嘧啶（PTU）治疗在血管内皮生长因子受体抑制和缺氧联合暴露后诱导大鼠实验性 PAH（Sugen-慢性缺氧（SuHx）模型）。甲状腺次全切除术可预防和 PTU 治疗逆转严重实验性 PAH 的发展。甲状腺素补充恢复了甲状腺切除术 SuHx 大鼠的 PAH 表型。甲状腺切除术对 PAH 的预防与细胞周转率降低、细胞外信号调节蛋白激酶 1 和 2 磷酸化减少以及 α(v)β(3)整合素、成纤维细胞生长因子 (FGF)-2 和 FGF 受体表达减少有关。甲状腺切除术减轻了缺氧诱导的肺动脉高压，但这种效应与肺血管阻力降低无关。这些数据表明，甲状腺激素允许 PAH 中的内皮细胞增殖。甲状腺疾病与 PAH 患者血管重构的发生或进展之间的因果关系仍有待确定。
