Differentiation and dedifferentiation of vascular smooth muscle cells (VSMCs) are essential processes of vascular development. VSMC have biosynthetic, proliferative, and contractile roles in the vessel wall. Alterations in the differentiated state of the VSMC play a critical role in the pathogenesis of a variety of cardiovascular diseases, including atherosclerosis, hypertension, and vascular stenosis. This review provides an overview of the current state of knowledge of molecular mechanisms involved in the control of VSMC proliferation, with particular focus on mitochondrial metabolism. Mitochondrial activity can be controlled by regulating mitochondrial dynamics, i.e., mitochondrial fusion and fission, and by regulating mitochondrial calcium handling through the interaction with the endoplasmic reticulum (ER). Alterations in both VSMC proliferation and mitochondrial function can be triggered by dysregulation of mitofusin-2, a small GTPase associated with mitochondrial fusion and mitochondrial–ER interaction. Several lines of evidence highlight the relevance of mitochondrial metabolism in the control of VSMC proliferation, indicating a new area to be explored in the treatment of vascular diseases.

We detected higher levels of MDA and PINP in primary aldosteronism patients, suggesting increased oxidative stress and myocardial fibrosis in these individuals. Treating primary aldosteronism patients reduced MDA and PINP levels, which may reflect the direct effect of aldosterone greater than endothelial oxidative stress and myocardial fibrosis, possibly mediated by a mineralocorticoid receptor.

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Chronic hypoxia exacerbates proliferation of pulmonary arterial smooth muscle cells (PASMC), thereby reducing the lumen of pulmonary arteries. This leads to poor blood oxygenation and cardiac work overload, which are the basis of diseases such as pulmonary artery hypertension (PAH). Recent studies revealed an emerging role of mitochondria in PAH pathogenesis, as key regulators of cell survival and metabolism. In this work, we assessed whether hypoxia-induced mitochondrial fragmentation contributes to the alterations of both PASMC death and proliferation. In previous work in cardiac myocytes, we showed that trimetazidine (TMZ), a partial inhibitor of lipid oxidation, stimulates mitochondrial fusion and preserves mitochondrial function. Thus, here we evaluated whether TMZ-induced mitochondrial fusion can prevent human PASMC proliferation in an in vitro hypoxic model. Using confocal fluorescence microscopy, we showed that prolonged hypoxia (48h) induces mitochondrial fragmentation along with higher levels of the mitochondrial fission protein DRP1. Concomitantly, both mitochondrial potential and respiratory rates decreased, indicative of mitochondrial dysfunction. In accordance with a metabolic shift towards non-mitochondrial ATP generation, mRNA levels of glycolytic markers HK2, PFKFB2 and GLUT1 increased during hypoxia. Incubation of PASMC with TMZ, prior to hypoxia, prevented all these changes and precluded the increase in PASMC proliferation. These findings were also observed using Mdivi-1 (a pharmacological DRP1 inhibitor) or a dominant negative DRP1 K38A as pre-treatments. Altogether, our data indicate that TMZ exerts a protective role against hypoxia-induced PASMC proliferation, by preserving mitochondrial function, thus highlighting DRP1-dependent morphology as a novel therapeutic approach for diseases such as PAH.