Obesity-associated Adiposomes Promote Smooth Muscle Cell Hypercontractility

Obesity is associated with chronic, low-grade inflammation, which triggers changes in adipose-derived extracellular vesicle (adiposome) composition. Our previous studies demonstrated that adiposomes from obese individuals induce endothelial dysfunction and impair microvascular flow-induced dilation. However, the direct effects of adiposomes on Ca 2+ signaling in vascular endothelial cells (ECs) and smooth muscle cells (SMCs), have not been explored. Abnormal Ca 2+ signaling plays a key role in the pathophysiology of vascular diseases such as hypertension. We hypothesize that obesity-associated adiposomes may disrupt Ca 2+ signaling in vascular cells by enhancing Ca 2+ influx in SMCs and/or inhibiting Ca 2+ signaling in ECs, collectively increasing vascular contractility. This disruption is thought to occur by inhibiting the ATP-sensitive K + channels (K ATP ) activity, which regulates membrane potential and calcium dynamics in vascular cells. Adiposomes were isolated from obese and lean subjects who underwent bariatric and elective surgeries via ultracentrifugation and characterized by nanoparticle tracking analysis. Ca 2+ recording (Fluo-4 AM), membrane potential (DiBAC4(3), and ROS activity were examined in cultured human adipose microvascular endothelial cells (HAMECs) and SMCs treated with adiposomes. Native SMCs and ECs were isolated from obese individuals. Calcium signals were analyzed using SparkAn software, and Fluorescence intensity changes were quantified. We found that acetylcholine-induced wave-like Ca 2+ events were significantly impaired in ECs isolated from obese individuals. In contrast, SMCs exhibited exaggerated Ca 2+ influx compared to lean controls. Pretreatment with adiposomes isolated from obese patients blunted acetylcholine-induced Ca 2+ signaling in HAMECs while acutely increasing Ca 2+ events in SMCs. Given that Ca 2+ signaling in both ECs and SMCs is influenced by membrane potential and regulated by K ATP channel activity, we investigated the K ATP role in adiposome-induced Ca 2+ influx. Using a voltage-sensitive probe (DiBAC4(3), we observed that hyperpolarization induced by pinacidil (a K ATP opener) was attenuated in cells pretreated with obese adiposomes. Conversely, a K ATP blocker glibenclamide-induced depolarization was enhanced. Consequently, the Ca 2+ signal induced by pinacidil in HAMECs was completely blunted upon pretreatment with these dysfunctional adiposomes. These preliminary data suggest dysfunctional adiposomes may inhibit K ATP channel activity in vascular ECs and SMCs, impairing Ca 2+ influx and promoting vascular contractility. In conclusion, this study uncovers a novel mechanism by which dysfunctional adiposomes promote vascular hypercontractility in obesity, highlighting the critical role of K ATP channels. Our ongoing research will further elucidate the molecular underpinnings of adiposome-mediated disruptions in Ca 2+ signaling, offering new therapeutic targets for treating vascular complications in obesity. This project was funded by the National Institute of Health grant number R01HL161386 and UIC-COM strategic Initiative 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.