Adenosine monophosphate-activated protein kinase inhibits vascular smooth muscle growth associated with vasculoproliferative disorders

Abstract

Vascular growth disorders are the major contributing factor to cardiovascular disease, the leading cause of morbidity and mortality worldwide. Aberrant vascular smooth muscle cell (VSMC) growth is a primary etiology foundational to the pathophysiology of this disorder. Recent findings support growth control of VSM by the metabolic sensor adenosine monophosphate-activated protein kinase (AMPK). Therefore, the aim of this project was to test our hypothesis that AMPK has ability to inhibit VSM growth in vivo by reducing neointima formation in rat carotid arteries following injury and in vitro by promoting VSMC cytostasis in rat thoracic aorta VSMCs. Our data reveal that local or systemic pre-treatment with the AMPK agonist AICAR significantly increases VSM AMPK activity and inhibits neointima formation in rat carotids following balloon injury. In cultured VSMCs AICAR also induced AMPK signaling and elicited cytostatic growth arrest via protein phosphatase 2A and cyclin- dependent kinase (CDK) inhibitor p21-mediated reduction of G0/G1 and S-phase cell cycling. Additionally, data reveal that phosphorylation of microfilament-associated vasodilator-activated serum phosphoprotein (VASP) by AMPK reduces pro-migratory events including microfilament elongation, actin strain-induced autophosphorylation of focal adhesion kinase (FAK), and focal adhesion turnover. Furthermore, AMPK reduced extracellular matrix proteolysis by matrix metalloproteinase (MMP)-9. Finally, evidence is provided for a positive signaling nexus between AMPK and cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) whereby these two systems cooperatively enhance the cytostatic actions of AMPK. Altogether, these results provide compelling evidence that AMPK regulates cytoskeletal/focal adhesion dynamics and cell cycle progression in an effort to reduce VSM growth in both in vitro and in vivo settings. These data increase our understanding of the role of this important metabolic regulator within VSMCs and provide support for its continued investigation in the metabolically- directed treatment of vasculoproliferative disorders.