Msx2 is required for vascular smooth muscle cells osteoblastic differentiation but not calcification in insulin-resistant ob/ob mice

Autor(es)

Andrade, Maria Claudina ; Carmo, Luciana S. ; Farias-Silva, Elisangela ; Liberman, Marcel

• Tipo de documento: Artigo Científico
• Fonte: ATHEROSCLEROSIS; v. 265, p. 14-21, OCT 2017.
• Citações Web of Science: 5

Resumo

Background and aims: Obesity and diabetes potentiate vascular calcification by increasing vascular smooth muscle cells osteoblastic differentiation mediated by the transcription factor Msx2 and bone morphogenetic protein-2 signaling. However, Bmp-2/Msx2 crosstalk to induce VSMC osteogenic phenotype transition and calcification is poorly understood in diabetes. We aimed to investigate mechanisms underlying Bmp-2-driven VSMC osteogenic differentiation and calcification in leptindeficient ob/ob mice. Methods: We incubated VSMC from ob/ob mice and wild type C57BL/6 littermates with or without Bmp2. We used loss-of-function experiments to investigate the role of Msx2 in Bmp-2-induced ob/ob VSMC osteochondrogenic differentiation and calcification by transfecting Msx2 siRNA into VSMC. Results: Baseline ob/ob VSMC and aorta showed increased Msx2, Runx2, alkaline phosphatase mRNA and protein expression, which further increased in Bmp-2-incubated ob/ob VSMC, therefore augmenting ob/ob VSMC calcification in comparison to wild type VSMC. Accordingly, signaling pathways to induce VSMC osteogenic differentiation, such as Smad1/5 phosphorylation increased in ob/ob versus wild type aorta. In comparison to wild type VSMC, Msx2 siRNA transfected VSMC decreased Bmp-2-dependent osteochondrogenic differentiation response by abrogating Msx2, Runx2, Alpl expression in ob/ob but not in wild type VSMC. Nonetheless, Msx2 inhibition did not decrease calcification in Bmp-2 stimulated ob/ob VSMC in vitro. Conclusions: Our data support a crucial role of Msx2 for ob/ob VSMC osteochondrogenic differentiation, however, Msx2 signaling alone is not sufficient for ob/ob VSMC calcification after Bmp-2 stimulation in vitro. These findings can be translated into novel perspectives for the understanding of the mechanisms and to provide therapeutic targets underlying vascular calcification in type 2 diabetes. (C) 2017 Elsevier B.V. All rights reserved. (AU)

• Processo FAPESP: 13/09652-0 - Mecanismos do remodelamento excêntrico associado à calcificação vascular na obesidade e resistência à insulina
• Beneficiário: Luciana Simao Do Carmo
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 13/09611-2 - Mecanismos do remodelamento excêntrico associado à calcificação vascular na obesidade e resistência à insulina
• Beneficiário: Marcel Liberman
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 10/07455-5 - Impacto da resistência à insulina na calcificação vascular
• Beneficiário: Marcel Liberman
• Modalidade de apoio: Auxílio à Pesquisa - Regular