Impaired vascular smooth muscle cell force-generating capacity and phenotypic deregulation in Marfan Syndrome mice

Autor(es):Mostrar menos -

Nolasco, Patricia ^[1] ; Fernandes, Carolina Goncalves ^[1] ; Ribeiro-Silva, Joao Carlos ^[2] ; Oliveira, Percillia V. S. ^[1] ; Sacrini, Mariana ^[3] ; de Brito, Isis Vasconcelos ^[3] ; De Bessa, Tiphany Coralie ^[1] ; Pereira, Lygia V. ^[4] ; Tanaka, Leonardo Y. ^[1] ; Alencar, Adriano ^[3] ; Martins Laurindo, Francisco Rafael ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Lab Biol Vasc, Inst Coracao InCor, Hosp Clin HCFMUSP, Fac Med, LIM 64 Biol Cardiovasc, Av Eneas C Aguiar, 44 Annex 2, 9th Floor, BR-05403904 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Fac Med, Hosp Clin HCFMUSP, Lab Genet Cardiol Mol, Inst Coracao InCor, Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Inst Fis, Lab Microrreol & Fisiol Mol, Sao Paulo, SP - Brazil

^[4] Univ Sao Paulo, Inst Biol, Lab Genet Mol, Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE; v. 1866, n. 1 JAN 1 2020.
• Citações Web of Science: 0

Resumo

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 mg Delta(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 alphaactin 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 dis-organized 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. (AU)

• Processo FAPESP: 18/07230-5 - Mecanismos subcelulares envolvidos na convergência entre homeostase mecânica e redox na regulação vascular
• Beneficiário: Leonardo Yuji Tanaka
• Linha de fomento: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 14/24511-7 - Mecanismos e implicações da sinalização via mTORC1 no fenótipo cardiovascular da Síndrome de Marfan
• Beneficiário: Patricia Nolasco Santos
• Linha de fomento: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 13/07937-8 - Redoxoma
• Beneficiário: Ohara Augusto
• Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 14/20595-1 - Dissulfeto Isomerase Proteica (PDI) como marcador de risco para trombose e/ou progressão acelerada de aterosclerose em pacientes com hipercolesterolemia familiar e em modelo experimental
• Beneficiário: Percíllia Victória Santos de Oliveira
• Linha de fomento: Bolsas no Brasil - Doutorado Direto