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Smooth muscle cell–specific fibronectin-EDA mediates phenotypic switching and neointimal hyperplasia
Manish Jain, … , Steven R. Lentz, Anil K. Chauhan
Manish Jain, … , Steven R. Lentz, Anil K. Chauhan
Published November 25, 2019
Citation Information: J Clin Invest. 2020;130(1):295-314. https://doi.org/10.1172/JCI124708.
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Research Article Vascular biology Article has an altmetric score of 6

Smooth muscle cell–specific fibronectin-EDA mediates phenotypic switching and neointimal hyperplasia

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Abstract

Fibronectin–splice variant containing extra domain A (Fn-EDA) is associated with smooth muscle cells (SMCs) following vascular injury. The role of SMC-derived Fn-EDA in SMC phenotypic switching or its implication in neointimal hyperplasia remains unclear. Herein, using human coronary artery sections with a bare metal stent, we demonstrate the expression of Fn-EDA in the vicinity of SMC-rich neointima and peri-strut areas. In mice, Fn-EDA colocalizes with SMCs in the neointima of injured carotid arteries and promotes neointima formation in the comorbid condition of hyperlipidemia by potentiating SMC proliferation and migration. No sex-based differences were observed. Mechanistic studies suggested that Fn-EDA mediates integrin- and TLR4-dependent proliferation and migration through activation of FAK/Src and Akt1/mTOR signaling, respectively. Specific deletion of Fn-EDA in SMCs, but not in endothelial cells, reduced intimal hyperplasia and suppressed the SMC synthetic phenotype concomitant with decreased Akt1/mTOR signaling. Targeting Fn-EDA in human aortic SMCs suppressed the synthetic phenotype and downregulated Akt1/mTOR signaling. These results reveal that SMC-derived Fn-EDA potentiates phenotypic switching in human and mouse aortic SMCs and neointimal hyperplasia in the mouse. We suggest that targeting Fn-EDA could be explored as a potential therapeutic strategy to reduce neointimal hyperplasia.

Authors

Manish Jain, Nirav Dhanesha, Prakash Doddapattar, Mehul R. Chorawala, Manasa K. Nayak, Anne Cornelissen, Liang Guo, Aloke V. Finn, Steven R. Lentz, Anil K. Chauhan

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Figure 3

Fn-EDA deletion in Apoe–/– mice suppresses synthetic phenotype and attenuates Akt1 signaling.

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Fn-EDA deletion in Apoe–/– mice suppresses synthetic phenotype and atten...
Aortic SMCs isolated from Apoe–/– and Fn-EDA–/– Apoe–/– mice were serum-starved for 48 hours and stimulated with or without PDGF-BB for 24 hours. (A) The left panels show representative immunostaining images for contractile proteins (SM22α, green; and SM-MHC, green) and synthetic proteins (vimentin, red; and osteopontin, red). Scale bars: 25 μm. The right panel shows quantification of the fluorescence intensity for SM22α, SM-MHC, vimentin, and osteopontin (n = 4 per group). (B) Representative immunoblots and densitometric analysis of SM22α, SM-MHC, vimentin, and osteopontin (n = 4 per group). Blots for SM22α, SM-MHC, and vimentin are from the same biological samples. (C) Quiescent aortic SMCs were stimulated with PDGF-BB (20 ng/mL) for 30 minutes, and cells were processed for Western blotting. Duplicate samples were run in the same gels, with the membrane cut in half, and then probed for total and phosphorylated proteins separately. Representative Western blots and densitometric analysis of Akt1, Akt2, mTOR, NF-κB, and β-actin (n = 6 per group). # 1 and # 2 are samples from 2 different experiments. (D) Serum-starved aortic SMCs were stimulated with PDGF-BB for 24 hours, and cell supernatant was used for quantification of TNF-α and IL-1β by ELISA (n = 5 per group). Values are expressed as mean ± SEM. Statistical analysis: unpaired Student’s t test.

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