Kuppusamy Maniselvan, Ottolini Matteo, Chen Yen-Lin, Daneva Zdravka, Li Jie, Heng-Mae Cheung Caroline, Rios Natalia, Radi Rafael, Garcia Gracie, Nwafor Divine, Park Min S, Tumanov Alexei V, Sonkusare Swapnil K
Robert M. Berne Cardiovascular Research Center (M.K., M.O., Y.-L.C., Z.D., J.L., C.H.-M.C., S.K.S.), University of Virginia, Charlottesville.
Departamento de Bioquímica, Facultad de Medicina (N.R., R.R.), Universidad de la República, Montevideo, Uruguay.
Circ Res. 2025 Aug 1. doi: 10.1161/CIRCRESAHA.124.326069.
Loss of endothelial function is a key contributor to obesity-induced hypertension. Obesity can cause chronic, low-grade inflammation, leading to abnormal blood vessel function. The release of inflammatory cytokines is commonly attributed to immune cells, but recent studies suggest that vascular cells can also release these cytokines. We tested the hypothesis that vascular wall-derived inflammatory cytokines act locally to impair endothelial function and elevate blood pressure in obesity.
The levels of inflammatory cytokines were analyzed in endothelial cells (ECs) and smooth muscle cells (SMCs) from small arteries of high-fat diet-fed mice and individuals with obesity. We utilized inducible, EC- or SMC-specific deletion and receptor inhibition studies to determine whether inflammatory signaling between SMCs and ECs can be targeted to improve endothelial function and lower blood pressure in obesity.
TNF (tumor necrosis factor) was selectively upregulated in SMCs from small arteries of obese mice and human subjects with obesity. TNF colocalized with TNFRI (TNF receptor I) at endothelial projections to SMCs or myoendothelial projections in obesity. SMC-specific deletion of TNF or EC-specific deletion of TNFRI improved endothelial function and lowered blood pressure in obese mice. Notably, deleting TNF from ECs or TNFRI from SMCs had no impact on endothelial function or blood pressure in obesity. Furthermore, the deletion of TNF from SMCs or TNFRI from ECs decreased the levels of inducible NO synthase and peroxynitrite, leading to enhanced activity of TRPV4 (transient receptor potential vanilloid 4) ion channels and improved endothelial function. In addition, specific inhibition of TNFRI also rescued endothelial function and lowered blood pressure in obesity.
Overall, these findings show that paracrine signaling from SMCs to ECs via TNF elevates blood pressure in obesity. Consequently, targeting smooth muscle TNF or endothelial TNFRI offers a potential approach for lowering blood pressure in obesity.
内皮功能丧失是肥胖诱导的高血压的关键促成因素。肥胖可导致慢性低度炎症，进而引起血管功能异常。炎性细胞因子的释放通常归因于免疫细胞，但最近的研究表明血管细胞也能释放这些细胞因子。我们检验了以下假设：血管壁来源的炎性细胞因子在局部发挥作用，损害肥胖状态下的内皮功能并升高血压。
分析了高脂饮食喂养小鼠和肥胖个体小动脉内皮细胞（ECs）和平滑肌细胞（SMCs）中炎性细胞因子的水平。我们利用诱导性、EC或SMC特异性缺失及受体抑制研究，以确定SMC和EC之间的炎性信号传导是否可作为靶点，来改善肥胖状态下的内皮功能并降低血压。
肥胖小鼠和肥胖人类受试者小动脉的SMC中，肿瘤坏死因子（TNF）选择性上调。在肥胖状态下，TNF与TNF受体I（TNFR I）在内皮细胞向SMC的突起或肌内皮突起处共定位。SMC特异性缺失TNF或EC特异性缺失TNFR I可改善肥胖小鼠的内皮功能并降低血压。值得注意的是，从ECs中删除TNF或从SMCs中删除TNFR I对肥胖状态下的内皮功能或血压没有影响。此外，从SMCs中删除TNF或从ECs中删除TNFR I可降低诱导型一氧化氮合酶和过氧亚硝酸盐的水平，导致瞬时受体电位香草酸亚型4（TRPV4）离子通道活性增强，内皮功能改善。此外，特异性抑制TNFR I也可挽救肥胖状态下的内皮功能并降低血压。
总体而言，这些发现表明，肥胖状态下通过TNF从SMC到EC的旁分泌信号传导会升高血压。因此，靶向平滑肌TNF或内皮TNFR I为降低肥胖状态下的血压提供了一种潜在方法。
