NETosis Drives Blood Pressure Elevation and Vascular Dysfunction in Hypertension

Area of Science:

• Cardiovascular Biology
• Immunology
• Cellular Physiology

Background:

• Neutrophil extracellular traps (NETs), comprising DNA, enzymes, and citrullinated histones, are released during NETosis.
• NETs are found in the aorta and kidneys of hypertensive individuals.
• Protein-arginine deiminase-4 (PAD4) is crucial for NETosis, and transient receptor potential cation channel subfamily V member 4 (TRPV4) is a mechanosensitive calcium channel in neutrophils.

Purpose of the Study:

• To investigate the role of NETosis in hypertension.
• To determine if NETosis contributes to endothelial cell (EC) dysfunction.
• To explore the involvement of TRPV4 and EC stretch in initiating NETosis.

Main Methods:

• Utilized NETosis-deficient Padi4 mice treated with angiotensin II (Ang II).
• Measured blood pressure, vascular reactivity, and NETosis via flow cytometry and immunofluorescence.
• Assessed EC function after exposure to citrullinated histone H3 and neutrophils treated with TRPV4 agonist.

Main Results:

• Padi4 mice showed reduced hypertension, aortic inflammation, and improved vascular relaxation.
• Hypertensive stretch of ECs cocultured with neutrophils increased NETosis and citrullinated histone H3 accumulation.
• Citrullinated histone H3 impaired EC-dependent vascular relaxation, and TRPV4 activation increased calcium influx and NETosis.

Conclusions:

• NETosis plays a role in hypertension pathogenesis.
• Endothelial cell stretch and TRPV4 are initiators of NETosis.
• Citrullinated histones drive endothelial cell dysfunction in hypertension.