Dysfunctional regulation of endothelial nitric oxide synthase (eNOS) expression in response to exercise in mice lacking one eNOS gene.

BACKGROUND: Previous data suggest that 1 endothelial NO synthase (eNOS) gene is sufficient to allow normal expression and function of eNOS under basal conditions. We hypothesized that this might not hold true for conditions known to increase eNOS gene expression, such as exercise. METHODS AND RESULTS: Male mice heterozygous for a disruption of the eNOS gene (eNOS(+/)(-)) and normal C56Bl/6J mice (eNOS(+/+)), 3 to 4 months of age, underwent exercise training for 3 weeks. Nontrained mice were exposed to the exercise environment (noise and vibration of the treadmill) without exercise for an identical period. In eNOS(+/+) mice (n=7), exercise increased aortic eNOS protein expression by 3.4+/-0.4-fold (P<0.002). This was associated with a greater vascular cGMP accumulation on stimulation with acetylcholine (P<0.05). Furthermore, exercise training increased eNOS mRNA (1.78+/-0.4-fold) and protein (1.76+/-0.17-fold) in left ventricular tissue, as determined by competitive reverse transcription-polymerase chain reaction and Western analysis (P<0.05 for both). In striking contrast, exercise had no effect on aortic eNOS expression and cGMP accumulation in eNOS(+/)(-) mice (P>0.05). Thus, although eNOS expression appears to be normal in eNOS(+/)(-) mice under basal conditions, these mice are unable to increase eNOS expression during exercise. CONCLUSIONS: These findings show that regulation of eNOS expression during exercise requires the presence of both alleles of the gene and may have implications for conditions in which polymorphisms of eNOS are present in only 1 allele in humans. These individuals may have a normal vascular reactivity under basal conditions but may be unable to adapt their vascular reactivity in response to exercise training.