AKT Mediates Adiponectin-Dependent Regulation of VSMC Phenotype

Area of Science:

• Cardiovascular Biology
• Molecular Biology
• Cell Biology

Background:

• Adiponectin (adipoq) is a crucial hormone for cardiovascular health, preserving vascular smooth muscle cell (VSMC) contractile function.
• Previous studies show conflicting results regarding adiponectin's role in atherosclerosis, highlighting a need for deeper mechanistic understanding.

Purpose of the Study:

• To elucidate the molecular mechanisms by which adiponectin regulates VSMC phenotype and function.
• To investigate the role of adiponectin in AKT signaling, extracellular matrix (ECM) remodeling, and metabolic pathways within VSMCs.

Main Methods:

• RNA sequencing of adiponectin-deficient (adipoq) and wild-type VSMCs from male aortas.
• Analysis of signaling pathways including AKT, AMPK, and TGF-β.
• Assessment of mitochondrial function, reactive oxygen species (ROS) production, and ECM gene expression.
• In vivo analysis of aortic protein expression, including sex-based differences.

Main Results:

• Adiponectin deficiency upregulates AKT activity, promoting VSMC proliferation and migration.
• AMPK activation partially mitigates proliferation and migration but does not restore contractile gene expression.
• Adiponectin deficiency impairs oxidative phosphorylation, increases glycolysis, and elevates mitochondrial ROS.
• Adiponectin influences ECM remodeling by downregulating MMP2/9 and upregulating DCN/ELN.
• Significant sex differences in aortic MMP3 and DCN expression were observed in vivo.

Conclusions:

• The AKT/MAPK/TGF-β network is a central regulator of VSMC phenotype, modulated by adiponectin.
• Adiponectin deficiency leads to detrimental changes in VSMC function and metabolism, contributing to cardiovascular pathology.
• Understanding these pathways offers potential therapeutic targets for cardiovascular diseases.