Breaking the redox-calcium loop: Pharmacology, physiology and therapeutic promise of disrupting the endothelial TRPV4-NOX2 complex

Abstract

Transient receptor potential vanilloid-4 (TRPV4) and NADPH oxidase-2 (NOX2) assemble into a calcium-redox signalosome that couples membrane mechanosensation to reactive‑oxygen signaling in endothelial cells, osteocytes and other mechanically active tissues. Recent work has mapped the interaction to a 12-residue amphipathic helix on the TRPV4 C-tail that docks onto an eight-residue B-loop motif in NOX2. Diet-induced obesity strengthens this handshake, amplifies vascular superoxide, disrupts barrier integrity and blunts vasodilation, whereas peroxynitrite-driven oxidation of the AKAP150 scaffold can uncouple the partners and raise blood pressure. Pharmacological and genetic studies now demonstrate that targeting the interface-rather than blocking the channel or oxidase outright-can reset vascular homeostasis. The small molecule M12 and a mini-helix Δ4 decoy both dismantle the complex in vivo, normalizing ROS levels, vascular permeability and tone without silencing basal TRPV4 current or NOX2 catalytic activity. A multi-tiered assay pipeline-spanning immuno-FRET, ROS/Ca²⁺ imaging, pressure myography and radiotelemetry-enables systematic vetting of emerging disruptors, while medicinal-chemistry, macrocyclic-peptide and degradomer strategies are poised to deliver clinic-ready leads. This first dedicated review synthesizes current knowledge of the TRPV4-NOX2 interface, its physiological and pathological roles, existing inhibitor chemotypes and the translational hurdles that must be cleared to exploit this signalosome as a precision target in cardiometabolic and inflammatory disorders.

Keywords: NOX2; Protein–protein interaction; Small-molecule disruptor; TRPV4; Vascular oxidative stress.