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 (NO_x), 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 NO_x were similar between genotypes at baseline, E₂ decreased NO_x 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.

在怀孕期间，雌激素（E ₂）通过增强一氧化氮（NO）依赖性血管舒张作用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（H ₂ S）并通过产生1-半胱氨酸来维持还原型与氧化型细胞内谷胱甘肽（GSH / GSSG）的比例来促进血管NO信号传导。因为氧化还原稳态可以影响NO信号传导，所以我们假设CSE通过调节局部细胞内半胱氨酸代谢和GSH / GSSG水平来促进氧化还原稳态来介导UBF的E ₂刺激。使用未怀孕的卵巢切除和野生型CSE（CSE KO）小鼠，我们对小鼠子宫和肾动脉进行了超声检查，以评估外源性E引起的血流变化₂刺激。我们量化了血清和子宫动脉NO代谢物（NO _x），血清氨基酸以及子宫和肾动脉GSH / GSSG。WT和CSE KO小鼠表现出相似的基线子宫和肾脏血流。与野生型不同，CSE KO小鼠未表现出预期的E ₂对UBF的刺激。肾血流量是Ë ₂不敏感的两个基因型。虽然血清和子宫动脉NO _X在基线基因型之间相似，E ₂降低NO _X在CSE KO血清。CSE KO血清中的半胱氨酸也较低，而瓜氨酸和高半胱氨酸水平则升高。Ë ₂和CSE缺失会加重子宫动脉GSH / GSSG的降低。相反，肾动脉GSH / GSSG对E ₂或CSE缺失不敏感。在一起，这些发现表明，CSE维持子宫动脉GSH / GSSG有助于子宫动脉中的硝化信号传导，并且是正常E ₂刺激UBF所必需的。这些数据对妊娠病理生理和特定血管床的选择性激素反应具有影响。