Paracrine Smooth Muscle-to-Endothelial Signaling via TNF Elevates Blood Pressure in Obesity

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.