Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/15640
Título
p38 MAPK priming boosts VSMC proliferation and arteriogenesis by promoting PGC1α-dependent mitochondrial dynamics.
Autor(es)
Fecha de publicación
2022-04-08
Cita
Sci Rep. 2022 Apr 8;12(1):5938
Idioma
Inglés
Tipo de documento
journal article
Resumen
Vascular smooth muscle cell (VSMC) proliferation is essential for arteriogenesis to restore blood flow after artery occlusion, but the mechanisms underlying this response remain unclear. Based on our previous findings showing increased VSMC proliferation in the neonatal aorta of mice lacking the protease MT4-MMP, we aimed at discovering new players in this process. We demonstrate that MT4-MMP absence boosted VSMC proliferation in vitro in response to PDGF-BB in a cell-autonomous manner through enhanced p38 MAPK activity. Increased phospho-p38 in basal MT4-MMP-null VSMCs augmented the rate of mitochondrial degradation by promoting mitochondrial morphological changes through the co-activator PGC1α as demonstrated in PGC1α-/- VSMCs. We tested the in vivo implications of this pathway in a novel conditional mouse line for selective MT4-MMP deletion in VSMCs and in mice pre-treated with the p38 MAPK activator anisomycin. Priming of p38 MAPK activity in vivo by the absence of the protease MT4-MMP or by anisomycin treatment led to enhanced arteriogenesis and improved flow recovery after femoral artery occlusion. These findings may open new therapeutic opportunities for peripheral vascular diseases.
MESH
Matrix Metalloproteinase 17 | p38 Mitogen-Activated Protein Kinases | Animals | Anisomycin | Cell Proliferation | Cells, Cultured | Mice | Mitochondrial Dynamics | Muscle, Smooth, Vascular | Myocytes, Smooth Muscle | Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Descripción
Funding was provided by the Spanish Ministerio de Ciencia e Innovación (AEI/FEDER, UE), SAF2017-83229-R and PID2020-112981RB-I00 (AGA), PID2020-114709RA-I00 (AGD), PID2019-104399RB-I00 (GS), RTI2018-093864-B-I00 (MM), PGC2018-098557-B-I00 (PB), PRE2019-088222 (JIJL) and the Spanish Ministerio de Educación, Cultura y Deporte, FPU15-05802 (LHM). ASE was supported by fellowships from Obra Social La Caixa, Ford-Apadrina La Ciencia and La Residencia de Estudiantes. AGD is an Atracción de Talento M1 Fellow from Comunidad de Madrid (Spain) [2019-T1BMD-14236].
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