Division of Pulmonary and Critical Care Medicine (T.N., L.S., D.S., A.T., P.N.K.) and the Departments of Pathology (G.J.B.) and Anesthesiology (J.R.T., R.G.P.), Stanford University Medical Center, Stanford, CA; and Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, China (L.Q.).
Circulation. 2014 Feb 11;129(6):692-703. doi: 10.1161/CIRCULATIONAHA.113.003734. Epub 2013 Nov 7.
Pulmonary endothelial injury triggers a reparative program, which in susceptible individuals is characterized by neointima formation, vascular narrowing, and the development of pulmonary arterial hypertension. The neointimal cells in human pathological plexiform lesions frequently coexpress smooth muscle α-actin and the endothelial von Willebrand antigen, creating a question about their cellular lineage of origin.
Experimental pulmonary hypertension with neointima formation develops in C57Bl/6 mice subjected to left pneumonectomy followed 1 week later by jugular vein injection of monocrotaline pyrrole (20 μg/μL and 1 μL/g; group P/MCTP). Compared with the group vehicle, by day 35, group P/MCTP developed higher right ventricular systolic pressure (54±5 versus 25±2 mm Hg; P<0.01) and right ventricular hypertrophy (0.58±0.16 versus 0.26±0.05; P<0.01). Transgenic vascular endothelial-cadherin Cre recombinase or Tie-2 Cre mice were intercrossed with mTomato/mGreen fluorescent protein double-fluorescent Cre reporter mice to achieve endothelial genetic lineage marking with membrane-targeted green fluorescent protein. In control mice, few endothelial lineage-marked cells lining the lumen of small pulmonary arteries demonstrate expression of smooth muscle α-actin. Concurrent with the development of pulmonary hypertension, endothelial lineage-marked cells are prominent in the neointima and exhibit expression of smooth muscle α-actin and smooth muscle myosin heavy chain. Human pulmonary arterial hypertension neointimal lesions contain cells that coexpress endothelial CD31 or von Willebrand antigen and smooth muscle α-actin.
Neointimal cells in pulmonary hypertension include contributions from the endothelial genetic lineage with induced expression of smooth muscle α-actin and smooth muscle myosin heavy chain.
肺血管内皮损伤会触发修复程序，在易感性个体中，该程序的特征是内膜形成、血管狭窄和肺动脉高压的发展。在人类病理性丛状病变中，内膜细胞经常共表达平滑肌α-肌动蛋白和血管内皮 von Willebrand 抗原，这引发了它们的细胞起源谱系问题。
在接受左肺切除术 1 周后，通过颈静脉注射单环毛蚓吡啶（20μg/μL 和 1μL/g；P/MCTP 组），C57Bl/6 小鼠会出现伴有内膜形成的实验性肺动脉高压。与对照组相比，P/MCTP 组在第 35 天出现更高的右心室收缩压（54±5 与 25±2mmHg；P<0.01）和右心室肥厚（0.58±0.16 与 0.26±0.05；P<0.01）。血管内皮钙黏蛋白 Cre 重组酶或 Tie-2 Cre 转基因小鼠与 mTomato/mGreen 荧光蛋白双荧光 Cre 报告小鼠杂交，以实现膜靶向绿色荧光蛋白的内皮遗传谱系标记。在对照组小鼠中，很少有内皮谱系标记的细胞沿小肺动脉管腔排列并表达平滑肌α-肌动蛋白。随着肺动脉高压的发展，内皮谱系标记的细胞在内膜中显著增加，并表达平滑肌α-肌动蛋白和平滑肌肌球蛋白重链。人类肺动脉高压内膜病变包含共表达内皮 CD31 或 von Willebrand 抗原和平滑肌α-肌动蛋白的细胞。
肺动脉高压中的内膜细胞包括内皮遗传谱系的贡献，其表达平滑肌α-肌动蛋白和平滑肌肌球蛋白重链。
