1. Impaired vascular smooth muscle cell force-generating capacity and phenotypic deregulation in Marfan Syndrome mice.
- Author
-
Nolasco P, Fernandes CG, Ribeiro-Silva JC, Oliveira PVS, Sacrini M, de Brito IV, De Bessa TC, Pereira LV, Tanaka LY, Alencar A, and Laurindo FRM
- Subjects
- Actins metabolism, Animals, Aorta metabolism, Aorta pathology, Aortic Aneurysm metabolism, Aortic Aneurysm pathology, Biomarkers metabolism, Cell Differentiation physiology, Cell Proliferation physiology, Cells, Cultured, Cytoskeleton metabolism, Cytoskeleton pathology, Disease Models, Animal, Female, Fibrillin-1 metabolism, Focal Adhesions metabolism, Focal Adhesions pathology, Male, Marfan Syndrome metabolism, Mice, Mice, Inbred C57BL, Muscle, Smooth, Vascular metabolism, Myocytes, Smooth Muscle metabolism, Phenotype, Proteomics methods, Marfan Syndrome pathology, Muscle, Smooth, Vascular pathology, Myocytes, Smooth Muscle pathology
- Abstract
Mechanisms whereby fibrillin-1 mutations determine thoracic aorta aneurysms/dissections (TAAD) in Marfan Syndrome (MFS) are unclear. Most aortic aneurysms evolve from mechanosignaling deregulation, converging to impaired vascular smooth muscle cell (VSMC) force-generating capacity accompanied by synthetic phenotype switch. However, little is known on VSMC mechanoresponses in MFS pathophysiology. Here, we investigated traction force-generating capacity in aortic VSMC cultured from 3-month old mgâ
lpn MFS mice, together with morpho-functional and proteomic data. Cultured MFS-VSMC depicted marked phenotype changes vs. wild-type (WT) VSMC, with overexpressed cell proliferation markers but either lower (calponin-1) or higher (SM alpha-actin and SM22) differentiation marker expression. In parallel, the increased cell area and its complex non-fusiform shape suggested possible transition towards a mesenchymal-like phenotype, confirmed through several markers (e.g. N-cadherin, Slug). MFS-VSMC proteomic profile diverged from that of WT-VSMC particularly regarding lower expression of actin cytoskeleton-regulatory proteins. Accordingly, MFS-VSMC displayed lower traction force-generating capacity and impaired contractile moment at physiological substrate stiffness, and markedly attenuated traction force responses to enhanced substrate rigidity. Such impaired mechanoresponses correlated with decreased number, altered morphology and delocalization of focal adhesions, as well as disorganized actin stress fiber network vs. WT-VSMC. In VSMC cultured from 6-month-old mice, phenotype changes were attenuated and both WT-VSMC and MFS-VSMC generated less traction force, presumably involving VSMC aging, but without evident senescence. In summary, MFS-VSMC display impaired force-generating capacity accompanying a mesenchymal-like phenotype switch connected to impaired cytoskeleton/focal adhesion organization. Thus, MFS-associated TAAD involves mechanoresponse impairment common to other TAAD types, but through distinct mechanisms., (Copyright © 2019 Elsevier B.V. All rights reserved.)- Published
- 2020
- Full Text
- View/download PDF