In endothelial cells fluid shear stress phosphorylates and activates AMPK which in turn phosphorylates and inhibits the HMG CoA reductase (HCR), via a mechanism dependent on nitric oxide (NO). Thus, fluid shear stress (12 dyn/cm2; 18 hours) and cerivastatin (18 hours, 3 nM) attenuated the bradykinin-induced activation of Ras and ERK1/2, which was reversed by mevalonate (1mM). Exposure of endothelial cells to fluid shear stress also decreased the expression of HCR mRNA levels. The shear stress- dependent decrease was abolished after eNOS inhibition (L- NAME 300 mM; 18 hours) as well as after inhibition of the guanylyl-cyclase (NS2028 10 mM, 18 hours) supporting again a NO-dependent mechanism. In femoral arteries of wild-type mice provided with a running wheel to perform voluntary exercise (3838±348 m/day for 7 days) HCR mRNA expression was decreased compared to sedentary mice. In the isolated hindlimb of the exercised (3 days) or cerivastastin-treated (0.25 or 2.5 mg/kg for 3 days) mice the bradykinin (a Ras-activating agonist)- induced vasodilation in perfusion pressure was significantly impaired compared to sedentary untreated mice. These data indicate that in endothelial cells, the increased formation of NO in response to shear stress decreases HCR activity and associated downstream signalling. This represents a further mechanism by which fluid shear stress exerts its anti-atherosclerotic effects.