Bok Rachael, Guerra Damian D, Lorca Ramón A, Wennersten Sara A, Harris Peter S, Rauniyar Abhishek K, Stabler Sally P, MacLean Kenneth N, Roede James R, Brown Laura D, Hurt K Joseph
Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, 12700 E. 19th Avenue, Aurora, CO, 80045, USA.
Department of Biology, University of Louisville, 2301 S. 3rd Street, Louisville, KY, 40292, USA.
Redox Biol. 2021 Apr;40:101827. doi: 10.1016/j.redox.2020.101827. Epub 2020 Dec 8.
During pregnancy, estrogen (E) 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 (HS) 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 E 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 E stimulation. We quantified serum and uterine artery NO metabolites (NO), 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 E stimulation of UBF. Renal blood flow was E-insensitive for both genotypes. While serum and uterine artery NO were similar between genotypes at baseline, E decreased NO in CSE KO serum. Cysteine was also lower in CSE KO serum, while citrulline and homocysteine levels were elevated. E and CSE deletion additively decreased GSH/GSSG in uterine arteries. In contrast, renal artery GSH/GSSG was insensitive to E 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 E stimulation of UBF. These data have implications for pregnancy pathophysiology and the selective hormone responses of specific vascular beds.
在怀孕期间，雌激素（E）通过增强一氧化氮（NO）依赖性血管舒张来刺激子宫动脉血流（UBF）。胱硫醚γ-裂解酶（CSE）通过产生硫化氢（HS）以及通过l-半胱氨酸的生成来维持细胞内还原型谷胱甘肽与氧化型谷胱甘肽的比例（GSH/GSSG），从而促进血管NO信号传导。由于氧化还原稳态可影响NO信号传导，我们推测CSE通过调节局部细胞内半胱氨酸代谢和GSH/GSSG水平来介导E对UBF的刺激，以促进氧化还原稳态。我们使用未怀孕的去卵巢野生型（WT）和CSE基因敲除（CSE KO）小鼠，对小鼠子宫和肾动脉进行微超声检查，以评估外源性E刺激后血流的变化。我们对血清和子宫动脉中的NO代谢产物（NO）、血清氨基酸以及子宫和肾动脉中的GSH/GSSG进行了定量分析。WT和CSE KO小鼠表现出相似的基线子宫和肾血流。与WT不同，CSE KO小鼠未表现出预期的E对UBF的刺激作用。两种基因型的肾血流对E均不敏感。虽然在基线时基因型之间血清和子宫动脉中的NO相似，但E使CSE KO血清中的NO降低。CSE KO血清中的半胱氨酸也较低，而瓜氨酸和同型半胱氨酸水平升高。E和CSE缺失在子宫动脉中对GSH/GSSG产生累加性降低作用。相反，肾动脉中的GSH/GSSG对E或CSE缺失不敏感。总之，这些发现表明CSE对子宫动脉GSH/GSSG的维持促进了子宫动脉中的硝化信号传导，并且是E对UBF正常刺激所必需的。这些数据对妊娠病理生理学以及特定血管床的选择性激素反应具有重要意义。
