Endothelial-to-mesenchymal transition drives atherosclerosis progression
Pei-Yu Chen, … , Martin A. Schwartz, Michael Simons
Pei-Yu Chen, … , Martin A. Schwartz, Michael Simons
Published October 26, 2015
Citation Information: J Clin Invest. 2015;125(12):4514-4528. https://doi.org/10.1172/JCI82719.
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Research Article Vascular biology

Endothelial-to-mesenchymal transition drives atherosclerosis progression

Abstract

The molecular mechanisms responsible for the development and progression of atherosclerotic lesions have not been fully established. Here, we investigated the role played by endothelial-to-mesenchymal transition (EndMT) and its key regulator FGF receptor 1 (FGFR1) in atherosclerosis. In cultured human endothelial cells, both inflammatory cytokines and oscillatory shear stress reduced endothelial FGFR1 expression and activated TGF-β signaling. We further explored the link between disrupted FGF endothelial signaling and progression of atherosclerosis by introducing endothelial-specific deletion of FGF receptor substrate 2 α (Frs2a) in atherosclerotic (Apoe–/–) mice. When placed on a high-fat diet, these double-knockout mice developed atherosclerosis at a much earlier time point compared with that their Apoe–/– counterparts, eventually demonstrating an 84% increase in total plaque burden. Moreover, these animals exhibited extensive development of EndMT, deposition of fibronectin, and increased neointima formation. Additionally, we conducted a molecular and morphometric examination of left main coronary arteries from 43 patients with various levels of coronary disease to assess the clinical relevance of these findings. The extent of coronary atherosclerosis in this patient set strongly correlated with loss of endothelial FGFR1 expression, activation of endothelial TGF-β signaling, and the extent of EndMT. These data demonstrate a link between loss of protective endothelial FGFR signaling, development of EndMT, and progression of atherosclerosis.

Authors

Pei-Yu Chen, Lingfeng Qin, Nicolas Baeyens, Guangxin Li, Titilayo Afolabi, Madhusudhan Budatha, George Tellides, Martin A. Schwartz, Michael Simons

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Figure 6

Effect of endothelial FGF signaling suppression on atherosclerosis in mice after 4 months of HFD.

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Effect of endothelial FGF signaling suppression on atherosclerosis in mi...
(A) Microphotographs of aortas from Apoe–/– and FRS2αECKO Apoe–/– mice (24 weeks of age) after 4 months of HFD in the en face preparation after staining with Oil Red O and quantification of lesion areas (10 mice per group). All data are shown as mean ± SD (***P < 0.001 compared with Apoe–/–; unpaired 2-tailed Student’s t test). (B) Representative examples of cross sections from the aortic root stained with Oil Red O and quantification of aortic root lesion areas (12 mice per group). Scale bar: 200 μm. Mean ± SD (**P < 0.01 compared with Apoe–/–; unpaired 2-tailed Student’s t test). (C and D) Representative images of Oil Red O– or Movat-stained brachiocephalic arteries and abdominal aortas from Apoe–/– and FRS2αECKO Apoe–/– mice (Apoe–/– mice, n = 12; FRS2αECKO Apoe–/– mice, n = 10). Scale bar: 100 μm. High-magnification images of the lesion shown in boxed areas are shown to the right. Scale bar: 50 μm. NC, necrotic core. Note circumferential plaque in FRS2αECKO Apoe–/– mice. (E) Measurement of lesion area (***P < 0.001 compared with Apoe–/–; unpaired 2-tailed Student’s t test). (F) Quantifications of the extent of fibrous cap and necrotic areas in brachiocephalic arteries and abdominal aortas of Apoe–/– and FRS2αECKO Apoe–/– mice (*P < 0.05; ***P < 0.001 compared with Apoe–/–; unpaired 2-tailed Student’s t test).