Transdifferentiation of pulmonary arteriolar endothelial cells into smooth muscle-like cells regulated by myocardin involved in hypoxia-induced pulmonary vascular remodelling

• Published in: International journal of experimental pathology Vol. 87; no. 6; pp. 463 - 474
• Main Authors: Zhu, Pengcheng, Huang, Lei, Ge, Xiaona, Yan, Fei, Wu, Renliang, Ao, Qilin
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.12.2006; Blackwell Science; Blackwell Science Inc
• Subjects: Actins - analysis; Actins - genetics; Animals; Arterioles; Biological and medical sciences; Biomarkers - analysis; Cell Differentiation; Cells, Cultured; endothelial cell; Endothelial Cells - metabolism; Endothelial Cells - pathology; Gene Expression Regulation; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - metabolism; Hypertension, Pulmonary - pathology; hypoxia; Hypoxia - genetics; Hypoxia - metabolism; Immunohistochemistry - methods; Investigative techniques, diagnostic techniques (general aspects); Male; Medical sciences; Models, Animal; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; myocardin; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Original; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Piperazines - therapeutic use; Pneumology; Pulmonary Artery - metabolism; Pulmonary Artery - pathology; pulmonary hypertension; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Purines; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Sildenafil Citrate; smooth muscle cell; Sulfones; Trans-Activators - genetics; Trans-Activators - metabolism; transdifferentiation; Vasodilator Agents - therapeutic use; Endothelial cell; Oxygen; smooth muscle cell; Respiratory disease; Lung; Cardiovascular disease; Smooth muscle; Respiratory system; Pulmonary hypertension; Myocyte; Vascular remodeling; Anatomic pathology; Regulation(control); Transdifférentiation; transdifferentiation; Hypoxia; myocardin
• ISSN: 0959-9673; 1365-2613
• DOI: 10.1111/j.1365-2613.2006.00503.x

Summary Myocardin gene has been identified as a master regulator of smooth muscle cell differentiation. Smooth muscle cells play a critical role in the pathogenesis of hypoxia‐induced pulmonary hypertension (PH) and pulmonary vascular remodelling (PVR). The purpose of this study was to investigate the change of myocardin gene expression in the pulmonary vessels of hypoxia‐induced PH affected by Sildenafil treatment and the involvement of endothelial cells transdifferentiation into smooth muscle cells in the process of hypoxia‐induced PH and PVR. Myocardin and relative markers were investigated in animal models and cultured endothelial cells. Mean pulmonary artery pressure (mPAP) was measured. Immunohistochemistry and immunofluorescence were used to show the expression of smooth muscle α‐actin (SMA), in situ hybridization (ISH) and reverse transcription polymerase chain reaction (RT‐PCR) were performed respectively to detect the myocardin and SMA expression at mRNA levels. Small interfering RNA (siRNA) induced suppression of myocardin in cultured cells. We confirmed that hypoxia induced the PH and PVR in rats. Sildenafil could attenuate the hypoxia‐induced PH. We found that myocardin mRNA expression is upregulated significantly in the hypoxic pulmonary vessels and cultured cells but downregulated in PH with Sildenafil treatment. The porcine pulmonary artery endothelial cells (PAECs) transdifferentiate into smooth muscle‐like cells in hypoxic culture while the transdifferentiation did not occur when SiRNA of myocardin was applied. Our results suggest that myocardin gene, as a marker of smooth muscle cell differentiation, was expressed in the pulmonary vessels in hypoxia‐induced PH rats, which could be downregulated by Sildenafil treatment, as well as in hypoxic cultured endothelial cells. Hypoxia induced the transdifferentiation of endothelial cells of vessels into smooth muscle‐like cells which was regulated by myocardin.