Metwally Elsayed, Mirza Imaduddin, Morsy Mohammed H, Mostafa Sarah M, Bianco Francesco M, Hassan Chandra, Masrur Mario A, Rosas Paola C, Levitan Irena, Raj Usha J, Layden Brian T, Mahmoud Abeer M
Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, College of Medicine, University of Illinois Chicago, Chicago, Illinois, USA.
Department of Cytology and Histology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt.
Compr Physiol. 2025 Oct;15(5):e70053. doi: 10.1002/cph4.70053.
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 Ca, 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 Ca 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 channel function and Ca-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.
器官间的相互作用，尤其是脂肪组织和脉管系统之间的相互作用，在肥胖诱导的心血管功能障碍中起关键作用。我们之前的研究表明，肥胖供体的脂肪源性细胞外囊泡（脂肪体）通过内皮功能障碍损害小动脉血管舒张，但它们对血管平滑肌细胞（VSMC）功能的影响仍不清楚。
从25名接受减肥手术和择期手术的肥胖受试者、12名瘦受试者以及高脂饮食诱导肥胖（DIO）小鼠（n = 40）中收集内脏脂肪组织。通过超速离心分离脂肪体，并使用压力肌动描记法评估小动脉肌源性张力。在VSMC中测量细胞内钙、膜电位和活性氧（ROS）。
肥胖小动脉比瘦对照表现出更大的肌源性张力，在暴露于肥胖脂肪体的健康血管中也观察到这种反应。肥胖受试者的天然VSMC显示乙酰胆碱诱导的钙波放大，在暴露于肥胖人类或DIO小鼠脂肪体的培养VSMC中也观察到这种反应。膜电位分析表明，肥胖脂肪体损害了KATP通道功能，减弱了吡那地尔诱导的超极化，同时增强了格列本脲介导的去极化。肥胖脂肪体还提高了VSMC中的ROS水平，通过细胞外ROS清除可降低ROS水平，使钾通道功能和钙内流正常化，从而改善肥胖标本中的动脉过度收缩。此外，减少肥胖脂肪体中的神经酰胺可降低其诱导过度收缩的能力，突出了神经酰胺作为肥胖诱导血管功能障碍的关键介质。
这些发现强调了肥胖中血管-脂肪相互作用的一种致病形式，其中脂肪体介导的信号改变了VSMC的兴奋性和血管张力。针对这种器官间通讯轴可能提供新的策略来逆转肥胖相关的血管并发症。
