17β-Estradiol Restores Endothelial Nitric Oxide Release to Shear Stress in Arterioles of Male Hypertensive Rats

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Abstract
Background —Endothelial nitric oxide (NO)–mediated responses are impaired in arterioles of male spontaneously hypertensive rats (SHR), but they are still present in female SHR. We hypothesized that in vitro incubation of arterioles of male SHR with estrogen will restore NO-mediated responses by upregulation of endothelial NO synthase. Methods and Results —Responses to increases in perfusate flow (from 0 to 25 μL/min) and to the calcium ionophore A23187 (5×10 −8 to 10 −6 mol/L), norepinephrine (NE; 10 −7 to 3×10 −7 mol/L), sodium nitroprusside (SNP; 10 −8 to 10 −6 mol/L), and adenosine (ADO; 10 −6 to 5×10 −5 mol/L) were studied in cannulated and pressurized gracilis muscle arterioles (≈75 μm in diameter) isolated from 12-week-old male SHR before and after incubation with 10 −9 mol/L 17β-estradiol (17β-E 2 ) for 16 to 18 hours. After incubation with 17β-E 2 , basal diameter of arterioles was significantly increased (by ≈10%), and flow-induced dilation was significantly enhanced (79.8±2.9 versus 103.7±3.7 μm at 25 μL/min), resulting in a lowered shear stress (62.0±9.1 versus 32.5±4.2 dyne/cm 2 ). Also, vasoconstrictions to A23187 were reversed to dilations (−18.7±2.2 versus 18.8±1.7 μm), and constrictions to NE were significantly attenuated (−30.7±3.0 versus −21.2±2.8 μm). These alterations were eliminated by ICI 182,780 (10 −7 mol/L), an estrogen receptor antagonist; 5,6-dichloro-1-β- d -ribofuranosylbenzimidazole (10 −5 mol/L), a transcription inhibitor; or N ω -nitro- l -arginine methyl ester (10 −4 mol/L), an inhibitor of NO synthase, whereas they were not affected by aminoguanidine (5×10 −5 mol/L), a specific inhibitor of inducible NO synthase. Arteriolar responses were not altered by incubation with 17α-estradiol. Conclusions —Estrogen, via a receptor-mediated pathway, upregulates endothelial NO synthase gene expression, leading to increased NO production, and restores the regulation of wall shear stress in arterioles of male SHR.