1. Elevated c-fos expression is correlated with phenotypic switching of human vascular smooth muscle cells derived from lower limb venous varicosities
- Author
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Li Li, Zhenyu Guo, Chentao Luo, Ting Zhu, and Wan Zhang
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Vascular smooth muscle ,Myocytes, Smooth Muscle ,Phenotypic switching ,030204 cardiovascular system & hematology ,Muscle, Smooth, Vascular ,Veins ,Varicose Veins ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Cell Movement ,Varicose veins ,medicine ,Humans ,030212 general & internal medicine ,Osteopontin ,Vein ,Cells, Cultured ,Aged ,Cell Proliferation ,biology ,business.industry ,Middle Aged ,Actins ,Up-Regulation ,Phenotype ,medicine.anatomical_structure ,Real-time polymerase chain reaction ,Lower Extremity ,Case-Control Studies ,biology.protein ,Female ,Surgery ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Proto-Oncogene Proteins c-fos ,Signal Transduction - Abstract
Background Lower limb venous varicosities (VVs) are clinically common; however, their molecular underpinnings are far from well elucidated. Previous studies have demonstrated that the phenotypic transition of vascular smooth muscle cells (VSMCs) plays a critical role in VV pathogenesis and that c-fos is upregulated in VSMCs from VVs. The present study investigated the histologic and cytologic changes in VVs and the correlation between c-fos upregulation and VSMC phenotypic switching. Methods Thirty-four patients with VVs (VV group) and 13 patients undergoing coronary artery bypass using autologous great saphenous vein segments (normal vein [NV] group) were enrolled in the present study. The great saphenous veins of both groups were harvested for subsequent experiments. Hematoxylin and eosin staining was performed for vein morphologic analysis. Real-time quantitative polymerase chain reaction, immunohistochemistry, and Western blot assays were used to assess mRNA and protein expression of c-fos, α-smooth muscle actin (α-SMA), and osteopontin (OPN). Simple linear regression was used to evaluate the correlation between c-fos and OPN/α-SMA. Primary VSMCs were isolated from both groups and cultured in vitro. A cell counting kit-8 assay and scratch-wound assay were used to analyze the proliferation and migration abilities of the cells, respectively. Results The mean age of the patients in the NV and VV groups was 61.4 ± 3.8 years and 59.5 ± 10.4 years, respectively. The vein cavities of the VV group were dilated, and the arrangement of the cells was disordered. The tunica media of the VV group was thicker than that of the NV group owing to the accumulation and proliferation of VSMCs. Significantly elevated mRNA levels of c-fos and OPN were observed in the VV group compared with the NV group, and a positive correlation was further demonstrated between the mRNA levels of c-fos and OPN/α-SMA (R2, 0.5524; P Conclusions Both mRNA and protein expression of c-fos were upregulated in VV specimens, and the phenotypic biomarkers (OPN/α-SMA) were altered concurrently. VSMCs derived from VVs showed increased proliferation and migration abilities. Upregulation of c-fos might play a role in the phenotypic switching of VSMCs and subsequently participate in the pathogenesis of VVs. Clinical Relevance C-fos is an immediate early gene owing to the transient and rapid change in its expression in response to stimuli. It is involved in the regulation of cell proliferation, cell growth, and cell movement. In the present study, varicose vein specimens showed increased mRNA and protein expression of c-fos, accompanied by altered phenotypic biomarkers. The upregulation of the c-fos gene in smooth muscle cells cultured from varicose vein specimens might be associated with phenotypic switching and functional disturbance. These results could contribute to the exploration of the molecular mechanisms underlying the pathogenesis of varicose veins and the development of new therapeutic strategies.
- Published
- 2021
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