NETosis contributes to hypertension and vascular dysfunction by promoting endothelial cell (EC) dysfunction and inflammation. In hypertension, neutrophils undergo NETosis, a process involving the release of DNA, enzymes, and citrullinated histones. PAD4, a calcium-dependent enzyme, is essential for NETosis, while TRPV4, a mechanosensitive calcium channel in neutrophils, plays a key role in initiating NETosis. Hypertensive stretch of ECs increases NETosis, and citrullinated histone H3 (H3-Cit) from neutrophils disrupts EC function and vascular relaxation. TRPV4 agonism increases intracellular calcium and NETosis in neutrophils. Padi4^-/- mice, deficient in PAD4, exhibit reduced hypertension, improved EC-dependent vascular relaxation, and decreased aortic inflammation. These findings highlight the role of NETosis in hypertension pathogenesis, with EC stretch and TRPV4 as key drivers. H3-Cit, a product of NETosis, activates ECs and contributes to vascular dysfunction. Targeting NETosis may offer new therapeutic approaches for hypertension and related cardiovascular diseases.NETosis contributes to hypertension and vascular dysfunction by promoting endothelial cell (EC) dysfunction and inflammation. In hypertension, neutrophils undergo NETosis, a process involving the release of DNA, enzymes, and citrullinated histones. PAD4, a calcium-dependent enzyme, is essential for NETosis, while TRPV4, a mechanosensitive calcium channel in neutrophils, plays a key role in initiating NETosis. Hypertensive stretch of ECs increases NETosis, and citrullinated histone H3 (H3-Cit) from neutrophils disrupts EC function and vascular relaxation. TRPV4 agonism increases intracellular calcium and NETosis in neutrophils. Padi4^-/- mice, deficient in PAD4, exhibit reduced hypertension, improved EC-dependent vascular relaxation, and decreased aortic inflammation. These findings highlight the role of NETosis in hypertension pathogenesis, with EC stretch and TRPV4 as key drivers. H3-Cit, a product of NETosis, activates ECs and contributes to vascular dysfunction. Targeting NETosis may offer new therapeutic approaches for hypertension and related cardiovascular diseases.