Regulation of vascular smooth muscle cell proliferation by the protease MT4-MMP in developmental and adult arteriogenesis

• Autores: Alvaro Sahún Español
• Directores de la Tesis: Alicia García Arroyo (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2021
• Idioma: inglés
• Número de páginas: 196
• Títulos paralelos:
  • Regulación de la proliferación de células de musculo liso vascular por la proteasa MT4-MMP en arteriogenesis durante el desarrollo y en adulto
• Tribunal Calificador de la Tesis: Juan Miguel Redondo Moya (presid.), Ana María Briones Alonso (secret.), Guadalupe Sabio Buzo (voc.), Yoshifumi Itoh (voc.), Patricia Boya Tremoleda (voc.)
• Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
• Materias:
  • Química
    • Bioquímica
      • Biología molecular
  • Ciencias médicas
    • Medicina interna
      • Cardiología
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Ischemic vascular diseases are characterized by the lack of blood flow, usually after arterial occlusion, leading to hypoxia and irreversible tissue damage. Currently considered a major clinical burden, new therapeutical strategies to confront them are highly needed. A detailed understanding of the formation of functional arterioles, both during physiological development (arterial morphogenesis) and in pathological adult settings (arteriogenesis), may pave the way for the efficient development of such therapies. Although proliferation of vascular smooth muscle cells (VSMCs) is crucial for arterioles to be formed, details about its regulation are still lacking. Our group previously showed that absence of MT4-MMP, a matrix metalloprotease highly expressed in VSMCs, led to enhanced VSMC proliferation in neonatal aorta. Hence, we investigated whether MT4-MMP genetic elimination may boost artery formation through an increase in VSMC proliferation both during physiological development (coronary arterial development) and in a pathological adult scenario (hindlimb ischemia). In the developing heart, we observed MT4-MMP expressed in epicardial-derived cells during early embryonic development and in the coronary VSMCs in postnatal stages (P8 neonates). Deletion of MT4-MMP resulted in enhanced VSMC proliferation and increased number of arterioles both in the developing postnatal heart and after cryoinjury performed in P1 neonates. In the adult setting, MT4-MMP expression was also detected in arterial VSMCs of the superficial adductor muscle. Both global and VSMC-specific MT4-MMP deletion led to enhanced blood flow recovery in the superficial adductor muscle, correlating with increased abundance of large remodeled arterioles, after permanent femoral artery ligation. In addition, in VSMC-specific MT4-MMP-deficient mice, the remodeled arterioles contained higher proportion of proliferating VSMCs. We investigated the underlying molecular mechanisms in vitro in VSMCs isolated from the aortic vessel wall. We first observed that MT4-MMP-deficient VSMCs presented a constitutive increased activation of the p38 MAPK that led to enhanced proliferation of VSMCs upon PDGF-BB stimulation. Moreover, this augmented basal p38 MAPK activation upregulated mitophagy flux in MT4-MMP-null VSMCs. Our findings point to MT4-MMP as a negative modulator of VSMC proliferation both during development and after hindlimb ischemia-triggered arteriogenesis. Specifically, MT4-MMP deletion provides an additional control of mitophagy through a p38-dependent pathway in VSMCs, an scenario that primes VSMCs and enables them to mount a boosted proliferative response increasing artery formation and ameliorating blood flow recovery upon hindlimb ischemia