Paracrine smooth muscle-to-endothelial signaling via TNF elevates blood pressure in obesity

Background: Endothelial dysfunction 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. Methods: We used flow cytometry to analyze the levels of inflammatory cytokines in freshly isolated endothelial (ECs) and smooth muscle cells (SMCs) from small arteries of normal and obese mice. Additionally, we investigated whether endothelium- or smooth muscle-specific deletion of tumor necrosis factor (TNF) or TNF receptor I (TNFRI), or inhibition of TNFRI, rescues endothelial function and reduces blood pressure in obese mice. We also assessed the contribution of vascular TNF signaling in impairing endothelial function in arteries from obese patients. Results: We report a surprising signaling mechanism within the vascular wall, whereby TNF from SMCs acts locally on endothelial TNFRI to impair endothelial function and elevate blood pressure in obesity. TNF was selectively upregulated in SMCs from small arteries of obese mice and patients. SMC-derived TNF activated endothelial TNFRI signaling to increase the levels of inducible nitric oxide synthase and peroxynitrite, a reactive nitrogen species, in ECs. Peroxynitrite impaired Ca 2+ -influx signals in ECs and attenuated endothelium-dependent vasodilation, elevating blood pressure. Deletion of smooth muscle TNF or endothelial TNFRI, or inhibition of TNFRI, rescued endothelial function and reduced blood pressure in obesity. Conclusion: Overall, these findings show that paracrine SMC-to-EC signaling 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. The National Institutes of Health to SKS (HL142808, HL167208, and HL146914) 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.