Activation of AMP-Activated Protein Kinase by 5-Aminoimidazole-4-Carboxamide-1-β- d -Ribofuranoside in the Muscle Microcirculation Increases Nitric Oxide Synthesis and Microvascular Perfusion

Abstract

Objective-To investigate the effects of activation of the AMP-activated protein kinase (AMPK) on muscle perfusion and to elucidate the mechanisms involved. Methods and Results-In a combined approach, we studied the vasoactive actions of AMPK activator by 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside (AICAR) on rat cremaster muscle resistance arteries (Ϸ100 m) ex vivo and on microvascular perfusion in the rat hindlimb in vivo. In isolated resistance arteries, AICAR increased Thr172 phosphorylation of AMPK in arteriolar endothelium, which was predominantly located in microvascular endothelium. AICAR induced vasodilation (19Ϯ4% at 2 mmol/L, PϽ0.01), which was abolished by endothelium removal, inhibition of NO synthase (with N-nitro-L-arginine), or AMPK (with compound C). Smooth muscle sensitivity to NO, determined by studying the effects of the NO donor S-nitroso-N-acetylpenicillamine (SNAP), was not affected by AICAR except at the highest dose. AICAR increased endothelial nitric oxide synthase activity, as indicated by Ser1177 phosphorylation. In vivo, infusion of AICAR markedly increased muscle microvascular blood volume (Ϸ60%, PϽ0.05), as was evidenced by contrast-enhanced ultrasound, without effects on blood pressure, femoral blood flow, or hind leg glucose uptake. Conclusion-Activation

AMPK Alpha 1-Induced RhoA Phosphorylation Mediates Vasoprotective Effect of Estradiol

“…The modulation of the vasoreactivity resulting from the AMPK-RhoA pathway and the proproliferative and -migrative effects of phosphorylated RhoA 7 suggest that the AMPK-RhoA pathway activation may help to counteract the healing defect observed during diabetic pathology. 39,40 By demonstrating that AMPK is an effector of E2, we show that AMPK-RhoA pathway participate to gender differences in vascular function. Women develop coronary heart disease on average 10 years later than men.…”

Endothelium-dependent vasorelaxation to the AMPK activator AICAR is enhanced in aorta from hypertensive rats and is NO and EDCF dependent

“…However, AMPK activation does not result in eNOS phosphorylation under some conditions (19,41), suggesting that AMPK activity and eNOS phosphorylation can be dissociated and that the influence of AMPK on NOmediated vasomotor function may also involve other mechanisms in addition to the Ser 1177 phosphorylation-mediated activation of eNOS. Although some studies infer that NO-dependent relaxation stimulated by AMPK-mediated activation of eNOS may be possible, there is limited evidence from previous studies that acute activation of AMPK is capable of generating functional vasodilatory outcomes by this mechanism in an intact blood vessel or in the context of an in vivo vascular system (3,4). Our data, along with the recently published work of Bradley et al (4), are some of the first to our knowledge to demonstrate an association between endothelium, NO-dependent relaxation and the activation of AMPK in isolated intact vessels.…”

Liraglutide prevents microvascular insulin resistance and preserves muscle capillary density in high-fat diet-fed rats

“…Second, AMPK activation improves mitochondria function and decreases oxidative stress, endoplasmic reticulum stress, and inflammation (36), and inhibition of inflammation reverses HFD-induced microvascular insulin resistance (48). Third, activation of AMPK by AICAR increases eNOS activity and vasodilates the resistance arteries ex vivo and recruits muscle microvasculature in vivo (9). Finally, AMPK signaling stimulates VEGF expression, regulates skeletal muscle capillarization (34,50), and inhibits hyperglycemia-induced endothelial apoptosis (23) and mitochondria reactive oxygen species production (26).…”