Tie2 Cre mediated changes in antioxidant activity modulates blood pressure and vascular reactivity: A role for Nrf2

Background

Excessive oxidative stress is well known to participate in the pathogenesis of hypertension. A major regulator of oxidative stress is the transcription factor Nuclear factor erythroid 2–related factor 2 (Nrf2). However, the role of Nrf2 in the pathogenesis of hypertension is not completely understood, especially at the endothelial cell level.

ObjectivesWe hypothesized that endothelial specific Nrf2 and its endogenous inhibitor Kelch-like ECH-associated protein 1 (Keap1) modulate vascular oxidative stress, vasomotor function and blood pressure.

Methods

We examined blood pressure responses to Angiotensin II (ANG II) and to L-arginine methyl ester (L-NAME) in male and female wildtype (WT), Nrf2 floxed Tie2 Cre + (Nrf2KO) and Keap1 floxed Tie2 Cre + mice (Keap1 KO). In addition, vasodilator (acetylcholine (Ach), Sodium nitroprusside (SNP) and vasoconstrictor (phenylephrine, PE) responses in isolated skeletal muscle vessels were examined. Male and female responses were analyzed separately.

Results

While there were no changes in baseline blood pressures between genotypes, responses to acute ANG II were enhanced in male Nrf2 KO mice and blunted in Keap1 KO mice in both males and females. Chronic ANG II increased vascular ROS, which was inhibited in vessels from Keap1 KO mice. Vascular responses to ACh and increased flow were blunted in vessels from Nrf2 KO mice and augmented in Keap1 KO mice in both male and female vessels. L-NAME blunted responses to both flow and ACh in both Nrf2 and Keap1 KO mice. Vasoconstrictor responses to PE were augmented in Nrf2 KO vessels and blunted in Keap1 KO vessels.

Conclusions

Tie2-mediated changes in Nrf2 is a significant modulator of vascular reactivity and a potential therapeutic target in hypertension by altering ROS and nitric oxide. Differences in chronic blood pressure modulation in males and females are likely to be due to extravascular mechanisms.