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Estrogen Selectively Up-Regulates eNOS and nNOS in Reproductive Arteries By Transcriptional Mechanisms

Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; charles.rosenfeld{at}utsouthwestern.edu

Cui Chen, MS

Tim Roy, BS

Xiao-Tie Liu, MD

Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas

Objective: To determine the mechanism(s) whereby daily and acute estradiol-17ß (E₂ß) exposure modifies endothelium-derived nitric oxide synthase (eNOS) and vascular smooth muscle (VSM) neuronal nitric oxide synthase (nNOS) in reproductive and nonreproductive arteries and to localize NOS isoform expression within the vessel wall.

Methods: Oophorectomized nonpregnant ewes received E₂ß (1 µg/kg per day) or no E₂ß for 5-6 days or acute E₂ß (1 µg/kg) on day 6-7 with or without daily E₂ß. Uterine, mammary, mesenteric, and femoral arteries were collected at completion of each study, adventitia were removed, and samples were frozen and stored at -80C. After separating endothelium and VSM, NOS isoform mRNA was measured using reverse transcription-polymerase chain reaction. VSM nNOS protein was determined by Western analysis.

Results: Basal eNOS and nNOS mRNA was greatest (P < .02) in reproductive artery endothelium and VSM, respectively. Daily E₂ß was required for maximum uterine vascular responses to acute E₂ß and was associated with increased reproductive artery endothelial eNOS mRNA (> 1.5-fold, P < .02) and uterine VSM nNOS mRNA (> 2.5-fold, P < .003) and protein (21%, P < .05). Acute E₂ß in the presence and absence of daily E₂ß also increased uterine eNOS 68% and 28% (P = .01), respectively within 90 minutes but did not affect VSM nNOS. Mammary eNOS increased 71% only after E₂ß withdrawal; VSM nNOS was unchanged. Neither NOS isoform was altered in nonreproductive arteries by daily or acute E₂ß.

Conclusion: Basal eNOS and nNOS isoform expression is greatest in arteries from reproductive tissues, and isoform responses to E₂ß are cell specific and transcriptionally regulated. Furthermore, optimal uterine vascular responses to acute E₂ß exposure require daily E₂ß exposure that enhances basal NOS expression and abundance.

Key Words: Uterine artery • mammary artery • mesenteric artery • vascular smooth muscle • endothelium

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