This study investigates the role of neutrophil extracellular traps (NETs) in hypertension and vascular dysfunction. Neutrophils, the most abundant leukocytes in circulation, undergo NETosis, a process that involves the expulsion of DNA and nuclear components, leading to the formation of NETs. PAD4 (protein-arginine deiminase-4) is essential for NETosis, while TRPV4 (transient receptor potential cation channel subfamily V member 4) is a mechanosensitive calcium channel expressed in neutrophils. The study hypothesized that NETosis contributes to hypertension through endothelial cell (EC) dysfunction. Key findings include: - **NETosis and Hypertension**: Padi4−/− mice, which lack PAD4, exhibit attenuated hypertension and improved EC-dependent vascular relaxation compared to wild-type mice. - **EC Stretch and NETosis**: Coculture of neutrophils with ECs and exposure to hypertensive uniaxial stretch increase NETosis and accumulation of citrullinated histone H3 (H3-Cit). - **H3-Cit and EC Dysfunction**: Treatment of ECs with H3-Cit leads to EC activation and disruption of EC-dependent vascular function. - **TRPV4 and NETosis**: Activation of TRPV4 in neutrophils increases intracellular calcium and induces NETosis. The study concludes that NETosis plays a crucial role in the pathogenesis of hypertension and vascular dysfunction, with EC stretch and TRPV4 acting as initiators of NETosis. Additionally, citrullinated histones are identified as drivers of EC dysfunction in hypertension. These findings suggest that targeting NETosis may be a potential therapeutic approach for treating hypertension and related cardiovascular diseases.This study investigates the role of neutrophil extracellular traps (NETs) in hypertension and vascular dysfunction. Neutrophils, the most abundant leukocytes in circulation, undergo NETosis, a process that involves the expulsion of DNA and nuclear components, leading to the formation of NETs. PAD4 (protein-arginine deiminase-4) is essential for NETosis, while TRPV4 (transient receptor potential cation channel subfamily V member 4) is a mechanosensitive calcium channel expressed in neutrophils. The study hypothesized that NETosis contributes to hypertension through endothelial cell (EC) dysfunction. Key findings include: - **NETosis and Hypertension**: Padi4−/− mice, which lack PAD4, exhibit attenuated hypertension and improved EC-dependent vascular relaxation compared to wild-type mice. - **EC Stretch and NETosis**: Coculture of neutrophils with ECs and exposure to hypertensive uniaxial stretch increase NETosis and accumulation of citrullinated histone H3 (H3-Cit). - **H3-Cit and EC Dysfunction**: Treatment of ECs with H3-Cit leads to EC activation and disruption of EC-dependent vascular function. - **TRPV4 and NETosis**: Activation of TRPV4 in neutrophils increases intracellular calcium and induces NETosis. The study concludes that NETosis plays a crucial role in the pathogenesis of hypertension and vascular dysfunction, with EC stretch and TRPV4 acting as initiators of NETosis. Additionally, citrullinated histones are identified as drivers of EC dysfunction in hypertension. These findings suggest that targeting NETosis may be a potential therapeutic approach for treating hypertension and related cardiovascular diseases.