Divergent effects of canonical and non‐canonical TGF‐β signalling on mixed contractile‐synthetic smooth muscle cell phenotype in human Marfan syndrome aortic root aneurysms
| Autor: | Itai Palmon, Yasushi Tashima, Paul Chang, Tiffany K Koyano, Cristiana Iosef, Grayson Burdon, Michael P. Fischbein, Jason Z. Cui, Adam J. Rubin, Jeffrey Trojan, Kevin J Jaatinen, G. Berry, Albert J. Pedroza |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Vascular smooth muscle Cell Myocytes Smooth Muscle Notch signaling pathway Apoptosis SMAD Matrix metalloproteinase Muscle Smooth Vascular Cell Line Marfan Syndrome 03 medical and health sciences Aortic aneurysm 0302 clinical medicine Transforming Growth Factor beta medicine Humans cardiovascular diseases 10. No inequality Receptor Notch3 Aorta Cell Proliferation Inflammation Cell growth Chemistry Cell Biology Original Articles medicine.disease Cell biology Aortic Aneurysm smooth muscle cell phenotype 030104 developmental biology medicine.anatomical_structure Phenotype 030220 oncology & carcinogenesis cardiovascular system Molecular Medicine Original Article Muscle Contraction Signal Transduction |
| Zdroj: | Journal of Cellular and Molecular Medicine |
| ISSN: | 1582-4934 1582-1838 |
| Popis: | Aortic root aneurysm formation is a cardinal feature of Marfan syndrome (MFS) and likely TGF‐β driven via Smad (canonical) and ERK (non‐canonical) signalling. The current study assesses human MFS vascular smooth muscle cell (SMC) phenotype, focusing on individual contributions by Smad and ERK, with Notch3 signalling identified as a novel compensatory mechanism against TGF‐β‐driven pathology. Although significant ERK activation and mixed contractile gene expression patterns were observed by traditional analysis, this did not directly correlate with the anatomic site of the aneurysm. Smooth muscle cell phenotypic changes were TGF‐β‐dependent and opposed by ERK in vitro, implicating the canonical Smad pathway. Bulk SMC RNA sequencing after ERK inhibition showed that ERK modulates cell proliferation, apoptosis, inflammation, and Notch signalling via Notch3 in MFS. Reversing Notch3 overexpression with siRNA demonstrated that Notch3 promotes several protective remodelling pathways, including increased SMC proliferation, decreased apoptosis and reduced matrix metalloproteinase activity, in vitro. In conclusion, in human MFS aortic SMCs: (a) ERK activation is enhanced but not specific to the site of aneurysm formation; (b) ERK opposes TGF‐β‐dependent negative effects on SMC phenotype; (c) multiple distinct SMC subtypes contribute to a ‘mixed’ contractile‐synthetic phenotype in MFS aortic aneurysm; and (d) ERK drives Notch3 overexpression, a potential pathway for tissue remodelling in response to aneurysm formation. |
| Databáze: | OpenAIRE |
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