Obesity-Associated Adiposomes Promote Vascular Smooth Muscle Cell Hypercontractility

Abstract

Background: Inter-organ crosstalk, particularly between adipose tissue and vasculature, plays a key role in obesity-induced cardiovascular dysfunction. Our previous work showed that adipose-derived extracellular vesicles (adiposomes) from obese donors impair arteriolar vasodilation through endothelial dysfunction, but their impact on vascular smooth muscle cell (VSMC) function remains unclear. Methods: Visceral adipose tissues were collected from 25 obese and 12 lean subjects undergoing bariatric and elective surgeries, and from high-fat diet-induced obesity (DIO) mice (n = 40). Adiposomes were isolated by ultracentrifugation, and arteriolar myogenic tone was assessed using pressure myography. Intracellular Ca2+, membrane potential, and reactive oxygen species (ROS) were measured in VSMCs. Results: Obese arterioles exhibited greater myogenic tone than lean controls, a response also observed in healthy vessels exposed to obese adiposomes. Native VSMCs from obese subjects showed amplified acetylcholine-induced Ca2+ waves, a response also observed in cultured VSMCs exposed to adiposomes from obese humans or DIO mice. Membrane potential analysis showed that obese adiposomes impaired KATP channel function, attenuating pinacidil-induced hyperpolarization while enhancing glibenclamide-mediated depolarization. Obese adiposomes also elevated ROS levels in VSMCs, which were reduced by extracellular ROS scavenging, normalizing KATP channel function and Ca2+-influx, thereby ameliorating arterial hypercontractility in obese specimens. Furthermore, depleting ceramides in obese adiposomes diminished their ability to induce hypercontractility, highlighting ceramide as a key mediator of obesity-induced vascular dysfunction. Conclusions: These findings underscore a pathogenic form of vascular–adipose crosstalk in obesity, where adiposome-mediated signaling alters VSMC excitability and vascular tone. Targeting this inter-organ communication axis may offer new strategies to reverse obesity-related vascular complications.