Treatment of hypertension by increasing impaired endothelial TRPV 4‐ KC a2.3 interaction

The currently available antihypertensive agents have undesirable adverse effects due to systemically altering target activity including receptors, channels, and enzymes. These effects, such as loss of potassium ions induced by diuretics, bronchospasm by beta‐blockers, constipation by Ca 2+ channel blockers, and dry cough by ACEI , lead to non‐compliance with therapies (Moser, 1990). Here, based on new hypertension mechanisms, we explored a new antihypertensive approach. We report that transient receptor potential vanilloid 4 ( TRPV 4) interacts with Ca 2+ ‐activated potassium channel 3 ( KC a2.3) in endothelial cells ( EC s) from small resistance arteries of normotensive humans, while EC s from hypertensive patients show a reduced interaction between TRPV 4 and KC a2.3. Murine hypertension models, induced by high‐salt diet, N(G)‐nitro‐ l ‐arginine intake, or angiotensin II delivery, showed decreased TRPV 4‐ KC a2.3 interaction in EC s. Perturbation of the TRPV 4‐ KC a2.3 interaction in mouse EC s by overexpressing full‐length KC a2.3 or defective KC a2.3 had hypotensive or hypertensive effects, respectively. Next, we developed a small‐molecule drug, JN c‐440, which showed affinity for both TRPV 4 and KC a2.3. JN c‐440 significantly strengthened the TRPV 4‐ KC a2.3 interaction in EC s, enhanced vasodilation, and exerted antihypertensive effects in mice. Importantly, JN c‐440 specifically targeted the impaired TRPV 4‐ KC a2.3 interaction in EC s but did not systemically activate TRPV 4 and KC a2.3. Together, our data highlight the importance of impaired endothelial TRPV 4‐ KC a2.3 coupling in the progression of hypertension and suggest a novel approach for antihypertensive drug development.