Mitochondrial Homeostasis in VSMCs as a Central Hub in Vascular Remodeling

Abstract

Vascular remodeling is a common pathological hallmark of many cardiovascular diseases. Vascular smooth muscle cells (VSMCs) are the predominant cell type lining the tunica media and play a crucial role in maintaining aortic morphology, integrity, contraction and elasticity. Their abnormal proliferation, migration, apoptosis and other activities are tightly associated with a spectrum of structural and functional alterations in blood vessels. Emerging evidence suggests that mitochondria, the energy center of VSMCs, participate in vascular remodeling through multiple mechanisms. For example, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)-mediated mitochondrial biogenesis prevents VSMCs from proliferation and senescence. The imbalance between mitochondrial fusion and fission controls the abnormal proliferation, migration and phenotypic transformation of VSMCs. Guanosine triphosphate-hydrolyzing enzymes, including mitofusin 1 (MFN1), mitofusin 2 (MFN2), optic atrophy protein 1 (OPA1) and dynamin-related protein 1 (DRP1), are crucial for mitochondrial fusion and fission. In addition, abnormal mitophagy accelerates the senescence and apoptosis of VSMCs. PINK/Parkin and NIX/BINP3 pathways alleviate vascular remodeling by awakening mitophagy in VSMCs. Mitochondrial DNA (mtDNA) damage destroys the respiratory chain of VSMCs, resulting in excessive ROS production and decreased ATP levels, which are related to the proliferation, migration and apoptosis of VSMCs. Thus, maintaining mitochondrial homeostasis in VSMCs is a possible way to relieve pathologic vascular remodeling. This review aims to provide an overview of the role of mitochondria homeostasis in VSMCs during vascular remodeling and potential mitochondria-targeted therapies.

Exploring a new mechanism between lactate and VSMC calcification: PARP1/POLG/UCP2 signaling pathway and imbalance of mitochondrial homeostasis

“…As an important part of the mitochondrial quality control system, the normal operation and coordination of mitochondrial ssion and mitophagy can protect the integrity of the inner and outer membrane structure of mitochondria, thereby maintaining the integrity of mtDNA and mitochondrial membrane potential (16,22). Once the mitochondrial structure is damaged and the damaged mitochondria cannot clear themselves in time, the damaged mitochondria will produce an ROS storm, destroy the redox balance, and then lead to cell death (33). However, it is still unclear as to how PARP1/POLG regulates UCP2.…”

Nanoparticle‐based therapeutic strategies for mitochondrial dysfunction in cardiovascular disease

“…65 Further, in CVD, diseased VSMC exhibit reduced mitochondrial DNA content and a decrease in oxygen consumption rate (OCR), limiting their contractile ability. 66,67 Dysregulation of Ca 2+ channel function by ROS similarly affects respiration in VSMC as cardiomyocytes by impeding Ca 2+ transport. 68 Ca 2+ dysregulation in VSMC can additionally promote an osteochondrogenic phenotype and the increase of vascular calcification, which is correlated with acute cardiovascular event propensity.…”

“…Preliminary studies have shown that targeting VSMC senescence by increasing transcription of Kruppel‐like factor (KLF5) can reduce mitochondrial fission 65 . Further, in CVD, diseased VSMC exhibit reduced mitochondrial DNA content and a decrease in oxygen consumption rate (OCR), limiting their contractile ability 66,67 . Dysregulation of Ca 2+ channel function by ROS similarly affects respiration in VSMC as cardiomyocytes by impeding Ca 2+ transport 68 .…”

S100 proteins in cardiovascular diseases

“…However, no studies on the relationship between S100A6 and VSMCs have been published. The changes in VSMC structure and function are closely related to the occurrence of cardiovascular diseases (Grootaert and Bennett 2021 ; Xia et al 2023 ). During the development of atherosclerosis, abnormal proliferation and migration of VSMCs and the synthesis of the extracellular matrix by these cells are important contributors to early vascular injury (Vacante et al 2021 ).…”