Unlike cardiac or skeletal muscle cells, vascular smooth muscle cells (VSMCs) retain a remarkable degree of plasticity. On environmental cues they can dedifferentiate from a quiescent contractile state towards phenotypes of increased proliferation and migration as well as secretory capacity and inflammation. This ability to transition between different phenotypes is a prerequisite for physiological vascular remodeling processes, but also plays a key role in the pathogenesis of virtually all vascular diseases. These vascular diseases, above all atherosclerosis resulting in myocardial infarction or stroke, are still the leading cause of death worldwide. Based on the respective metabolic requirements of proliferating versus quiescent cells it was hypothesised that VSMCs undergo metabolic changes during dedifferentiation. Therefore, the aim of this study was to investigate the metabolic adaptions VSMCs exhibit during phenotypic transition and identify possible regulators thereof. Utilising two in vitro models and one in vivo model for VSMC dedifferentiation, this study showed that dedifferentiated VSMCs shift their energy generation from mitochondrial respiration towards elevated glycolysis and lactate production, reminiscent of the Warburg effect observed in cancer cells. Dedifferentiated VSMCs also displayed reduced expression of genes involved in mitochondrial respiration, lower mitochondrial abundance and altered mitochondrial shape, indicating a strong association between mitochondrial homeostasis and VSMC plasticity. The second objective of this study was to investigate whether intervention in VSMC metabolism would affect VSMC plasticity and vascular remodeling. Two known regulators of metabolism, Sirt6 and Sirt7, were chosen for their regulatory function in glucose and mitochondrial metabolism, respectively. The effects of VSMC specific knock-outs of Sirt6 and Sirt7 on VSMC dedifferentiation and proliferation were assessed in vitro and in vivo. Both sirtuins were expected to display atheroprotective functions. This could be confirmed for Sirt7 as the VSMC-specific knock-out of Sirt7 resulted in elevated neointima formation in a carotid artery ligation mouse model and increased plaque sizes in an ApoE-/- atherosclerosis mouse model. VSMC-specific knock-out of Sirt6 did not impact both these parameters. Contrary to expectations, the effects of the Sirt7 knock-out did not seem to be mediated by regulation of mitochondrial homeostasis. The atheroprotective role shown in this study, nevertheless renders Sirt7 an interesting target for the treatment of vascular diseases.
