The AMP-Related Kinase (AMPK) Induces Ca2+-Independent Dilation of Resistance Arteries by Interfering With Actin Filament Formation.
Circ Res. 2017 Jul 7;121(2):149-161. doi: 10.1161/CIRCRESAHA.116.309962. Epub 2017 Jun 6.
|Authors/Editors:||Schubert KM, Qiu J, Blodow S, Wiedenmann M, Lubomirov LT, Pfitzer G, Pohl U, Schneider H.|
RATIONALE: Decreasing Ca2+ sensitivity of vascular smooth muscle (VSM) allows for vasodilation without lowering of cytosolic Ca2+. This may be particularly important in states requiring maintained dilation such as hypoxia. AMPK is an important cellular energy sensor in VSM. Regulation of Ca2+ sensitivity usually is attributed to myosin light chain phosphatase (MLCP) activity but findings in non-VSM identified changes in the actin cytoskeleton. The potential role of AMPK in this setting is widely unknown.
OBJECTIVE: To assess the influence of AMPK on the actin cytoskeleton in VSM of resistance arteries with regard to potential Ca2+ desensitization of VSM contractile apparatus.
METHODS AND RESULTS: AMPK induced a slowly developing dilation at unchanged cytosolic Ca2+ levels in KCl-constricted intact arteries isolated from mouse mesenteric tissue. This dilation was not associated with changes in phosphorylation of myosin light chain or of MLCP regulatory subunit. Using ultracentrifugation and confocal microscopy we found that AMPK induced depolymerization of filamentous actin (F-actin). Imaging of arteries from LifeAct mice showed F-actin rarefaction in the mid-cellular portion of VSM. Immunoblotting revealed that this was associated with activation of the actin severing factor cofilin. Co-immunoprecipitation experiments indicated that AMPK leads to the liberation of cofilin from 14-3-3 protein.
CONCLUSIONS: AMPK induces actin depolymerization which reduces vascular tone and the response to vasoconstrictors. Our findings demonstrate a new role of AMPK in the control of actin cytoskeletal dynamics, potentially allowing for long term dilation of microvessels without substantial changes in cytosolic Ca2+.