Obesity-Associated Adiposomes Promote Vascular Smooth Muscle Cell Hypercontractility

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.

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.

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 K_ATP 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.

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.