A Skeletal Muscle-Mediated Anticontractile Response on Vascular Tone: Unraveling the Lactate-AMPK-NOS1 Pathway in Femoral Arteries
Background: The regulation of vascular tone by perivascular tissues involves a complex interaction of various paracrine factors. In this study, we investigate the anti-contractile effect of skeletal muscle surrounding the femoral and carotid arteries, as well as the underlying mechanisms.
Methods: Using male and female Wistar rats, we observed that serotonin, phenylephrine, and U-46619 induced a concentration-dependent vasoconstrictor response in femoral artery rings. Interestingly, this response was diminished when the femoral artery was surrounded by skeletal muscle, regardless of sex. No anti-contractile effect was noted when the carotid artery was exposed to its surrounding skeletal muscle. This effect in the femoral artery persisted even in the absence of the endothelium and when the muscle was detached from the artery. Additionally, the skeletal muscle surrounding the femoral artery exerted an anti-contractile effect on other vascular beds, including basilar, mesenteric, and carotid arteries.
Results: We confirmed the involvement of lactate in this effect by using inhibitors of lactate dehydrogenase and the 1/4 monocarboxylate transporter. Both inhibitors abolished the anti-contractile effect. However, lactate did not directly cause vasodilation. Instead, lactate activated 5′ AMP-activated protein kinase (AMPK) and neuronal nitric oxide synthase (NOS1) in the skeletal muscle. The use of Nω-propyl l-arginine, a specific inhibitor of NOS1, prevented the anti-contractile effect and the lactate-induced phosphorylation of NOS1 at the stimulatory serine site (1417) in primary skeletal muscle cells. Furthermore, phosphorylation of NOS1 was reduced with Bay-3827, a selective AMPK inhibitor.
Conclusion: The skeletal muscle surrounding the femoral artery acts as a potent paracrine and endocrine organ that modulates vascular tone in both sexes. The anti-contractile effect is dependent on muscle fiber type and/or anatomical location, rather than the type of artery or its associated endothelium. Mechanistically, the effect is mediated through the lactate-AMPK-phospho-NOS1Ser1417-NO signaling axis.