NOX5-induced uncoupling of endothelial NO synthase is a causal mechanism and theragnostic target of an age-related hypertension endotype

Hypertension is the most important cause of death and disability in the
elderly. In 9 out of 10 cases, the molecular cause, however, is unknown.
One mechanistic hypothesis involves impaired endothelium-dependent
vasodilation through reactive oxygen species (ROS) formation. Indeed, ROS
forming NADPH oxidase (Nox) genes associate with hypertension, yet target
validation has been negative. We re-investigate this association by
molecular network analysis and identify NOX5, not present in rodents, as a
sole neighbor to human vasodilatory endothelial nitric oxide (NO)
signaling. In hypertensive patients, endothelial microparticles indeed
contained higher levels of NOX5—but not NOX1, NOX2, or NOX4—with a bimodal
distribution correlating with disease severity. Mechanistically, mice
expressing human Nox5 in endothelial cells developed—upon aging—severe
systolic hypertension and impaired endothelium-dependent vasodilation due
to uncoupled NO synthase (NOS). We conclude that NOX5-induced uncoupling
of endothelial NOS is a causal mechanism and theragnostic target of an
age-related hypertension endotype. Nox5 knock-in (KI) mice represent the
first mechanism-based animal model of hypertension.