Adiponectin is a critical regulator of flow-mediated vasodilation in resistance arterioles of skeletal muscle

Obesity is a major risk factor in the progression of many cardiovascular diseases and often contributes to the disruption microvascular health mainly through endothelial dysfunction. Adiponectin, which is the most abundant adipokine, regulates endothelial function by regulating ceramide and sphingosine-1-phosphate (S1P) signaling. More specifically, adiponectin binds to cell surface receptors (AdipoR1 and AdipoR2) and activates endothelial ceramidase activity, which converts ceramide to S1P. This is critical because ceramide promotes production of reactive oxygen species, while S1P enhances the activity of endothelial nitric oxide synthase, which supports mechanotransduction and endothelium-dependent vasodilation. Therefore, we hypothesized that acute depletion of adiponectin impairs endothelium-dependent, flow-induced vasodilation by disrupting S1P signaling. To investigate this, first-order arterioles (70–125 μm) from the gastrocnemius muscle of adult male and female WT or inducible adiponectin knockout (AdipoKO) mice were isolated for evaluation of vasodilatory responses to intraluminal flow at constant pressure. Flow-induced vasodilation was evaluated at baseline and in the presence of N, N-Dimethylsphingosine (DMS) to block S1P production. At baseline, flow-induced vasodilation was significantly lower in arterioles from AdipoKO mice as compared to arterioles from WT mice. Blockade of S1P with DMS substantially reduced flow-induced vasodilation in arterioles from both male and female WT mice, indicating a strong reliance on S1P signaling. DMS also decreased flow-induced dilation in arterioles from male and female AdipoKO mice, but to a lesser degree than in WT mice. S1P inhibition eliminated the differences in flow-induced vasodilation in arterioles from male WT and AdipoKO mice. In contrast, in arterioles from female mice, in the presence of S1P inhibition, flow-induced vasodilation was lower in WT as compared to AdipoKO mice. These results indicate that acute depletion of adiponectin diminishes flow-mediated vasodilation of skeletal muscle arterioles. Furthermore, this impairment of flow-mediated vasodilation, induced by acute knockout of adiponectin, is associated with sex-specific disruption of S1P signaling. Taken together, our study highlights the critical role of adiponectin in regulating endothelial S1P signaling, which in turn governs mechanotransduction and endothelium-dependent vasodilation in skeletal muscle arterioles. NIH R01HL166591 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.