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Endothelial dysfunction in small arteries plays a pivotal role in obesity-induced hypertension. Recent investigations have unveiled the detrimental impact of peroxynitrite, a reactive nitrogen species, on endothelium calcium signaling and vasodilation. Vascular inflammation has emerged as a crucial contributor to the pathogenesis of cardiovascular disorders. In this regard, the inflammatory cytokine, tumor necrosis factor (TNF), has been linked to peroxynitrite formation and endothelial dysfunction. Although TNF signaling in cardiovascular disorders is mainly attributed to immune cells, recent studies suggest that endothelial cells (ECs) and smooth muscle cells (SMCs) also produce TNF. We hypothesized that TNF derived from the vascular wall acts locally to inhibit endothelium-dependent vasodilation in obesity. Male C57BL6J mice fed a high-fat diet (HFD, 60% kcal fat) for 14 weeks showed higher blood pressures that normal chow diet (NCD)-fed mice. Flow cytometry and mRNA expression studies showed an increase in TNF levels in freshly isolated SMCs from small mesenteric arteries (MAs) in HFD mice compared to NCD mice. However, TNF levels in ECs were not different between HFD or NCD mice. Control and EC-specific TNF knockout (TNF ECKO ) mice showed a similar increase in blood pressure after HFD feeding. However, HFD feeding failed to elevate blood pressure in SMC-specific TNF knockout (TNF SMCKO ) mice, suggesting a critical role for SMC TNF in blood pressure elevation in HFD mice. Both TNF SMCKO and TNF ECKO showed a similar increase in body weight after HFD feeding when compared to control mice, suggesting that differences in weight gain did not contribute to lower blood pressure in obese TNF SMCKO mice. The pro-inflammatory effects of TNF are primarily attributed to TNF receptor-I (TNFRI) signaling. Therefore, we postulated that TNF released from SMCs acts locally on EC TNFRI to impair endothelium-dependent vasodilation. EC-specific TNFRI deletion (TNFRI ECKO ) reduced blood pressure, whereas SMC-specific TNFRI deletion (TNFRI SMCKO ) had no effect on blood pressure after HFD feeding. These findings collectively underline the critical role of SMC-derived TNF and endothelial TNFRI in driving blood pressure elevation in diet-induced obesity. Consistent with these data, endothelium-dependent vasodilation in response to acetylcholine markedly improved in obese TNF SMCKO and TNFRI ECKO mice compared to obese control mice. Previous studies showed that decreased Ca 2+ influx through endothelial TRPV4 (transient receptor potential vanilloid 4) channels contributes to endothelia dysfunction and blood pressure elevation in obese mice. The activity of TRPV4 channels was improved in ECs from HFD-fed TNF SMCKO and TNFRI ECKO mice. Additionally, the levels of endothelial peroxynitrite were diminished in obese TNF SMCKO and TNFRI ECKO mice, ameliorating the peroxynitrite-dependent impairment of endothelial function. Furthermore, treatment with a selective TNFRI signaling inhibitor (R7050, 10 mg/kg, intraperitoneally, once daily for 14 days) restored blood pressure to normal levels in HFD-fed obese mice but had no effect on the blood pressure in NCD-fed mice. R7050 treatment also restored endothelium-dependent dilation of MAs and the activity of TRPV4 channels in ECs. Collectively, our findings identify a critical role of local TNF-TNFRI signaling in the vascular wall in obesity-induced impairment of endothelial function and blood pressure elevation. The National Institutes of Health to SKS (HL146914, HL142808, and HL147555). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Kuppusamy et al. (Wed,) studied this question.