Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, 12700 E. 19th Avenue, Aurora, CO, 80045, USA
Damian D. Guerra
Department of Biology, University of Louisville, 2301 S. 3rd Street, Louisville, KY, 40292, USA
Ramón A. Lorca
Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, 12700 E. 19th Avenue, Aurora, CO, 80045, USA
Sara A. Wennersten
Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, 12700 E. 19th Avenue, Aurora, CO, 80045, USA
Peter S. Harris
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 E. Montview Blvd, Aurora, CO, 80045, USA
Abhishek K. Rauniyar
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 E. Montview Blvd, Aurora, CO, 80045, USA
Sally P. Stabler
Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, 12700 E. 19th Avenue, Aurora, CO, 80045, USA
Kenneth N. MacLean
Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado Anschutz Medical Campus, 12700 E. 19th Avenue, Aurora, CO, 80045, USA
James R. Roede
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 E. Montview Blvd, Aurora, CO, 80045, USA
Laura D. Brown
Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Perinatal Research Center, 13243 E. 23rd Avenue, Aurora, CO, 80045, USA
K. Joseph Hurt
Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, 12700 E. 19th Avenue, Aurora, CO, 80045, USA; Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, 12700 E. 19th Avenue, Aurora, CO, 80045, USA; Corresponding author. Mail Stop 8613, 12700 E. 19th Avenue, Aurora, CO, 80045, USA.
During pregnancy, estrogen (E2) stimulates uterine artery blood flow (UBF) by enhancing nitric oxide (NO)-dependent vasodilation. Cystathionine γ-lyase (CSE) promotes vascular NO signaling by producing hydrogen sulfide (H2S) and by maintaining the ratio of reduced-to-oxidized intracellular glutathione (GSH/GSSG) through l-cysteine production. Because redox homeostasis can influence NO signaling, we hypothesized that CSE mediates E2 stimulation of UBF by modulating local intracellular cysteine metabolism and GSH/GSSG levels to promote redox homeostasis. Using non-pregnant ovariectomized WT and CSE-null (CSE KO) mice, we performed micro-ultrasound of mouse uterine and renal arteries to assess changes in blood flow upon exogenous E2 stimulation. We quantified serum and uterine artery NO metabolites (NOx), serum amino acids, and uterine and renal artery GSH/GSSG. WT and CSE KO mice exhibited similar baseline uterine and renal blood flow. Unlike WT, CSE KO mice did not exhibit expected E2 stimulation of UBF. Renal blood flow was E2-insensitive for both genotypes. While serum and uterine artery NOx were similar between genotypes at baseline, E2 decreased NOx in CSE KO serum. Cysteine was also lower in CSE KO serum, while citrulline and homocysteine levels were elevated. E2 and CSE deletion additively decreased GSH/GSSG in uterine arteries. In contrast, renal artery GSH/GSSG was insensitive to E2 or CSE deletion. Together, these findings suggest that CSE maintenance of uterine artery GSH/GSSG facilitates nitrergic signaling in uterine arteries and is required for normal E2 stimulation of UBF. These data have implications for pregnancy pathophysiology and the selective hormone responses of specific vascular beds.
