p38 MAPK priming boosts VSMC proliferation and arteriogenesis by promoting PGC1α-dependent mitochondrial dynamics

Abstract

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.

Identification of the microRNA alterations in extracellular vesicles derived from human haemorrhoids

“…The MAPK pathway is involved in angiogenesis during myocardial infarction (Zhang et al., 2022 ). Priming of p38 MAPK activity enhanced arteriogenesis after femoral artery occlusion (Sahún‐Español et al., 2022 ). Vascular hyperplasia and oedema are particularly obvious in haemorrhoids (Fox et al., 2014 ; Sugerman, 2014 ).…”

Exploring the potential mechanism of Simiao Yongan decoction in the treatment of diabetic peripheral vascular disease based on network pharmacology and molecular docking technology

“…[ 44 ] Researchers have validated in mice lacking the MT4-MMP protease that stimulating p38 MAPK activity can enhance arteriogenesis and improve blood supply after peripheral arterial occlusion. [ 45 ] FOX protein is a winged helix family of DNA-binding region transcription factors. It plays an important role in carbohydrate and fat metabolism, biological aging and immune regulation, development, and disease in mammals.…”

Molecular Mechanisms Driven by MT4-MMP in Cancer Progression

“…Whether MT4-MMP-periostin axis plays a role in tumor cell development and progression deserves further investigation. More recently, the absence of MT4-MMP has been shown to promote proliferation in vascular smooth muscle cells and the formation of collateral arterioles by induction of p38 MAPK signaling and mitochondria dynamics particularly in contexts of hypoxia or starvation (Figure 1A) [63]. The relevance of this pathway in tumors presenting heterogeneous hypoxia might be an interesting aspect to investigate.…”