Frontiers in immunology · 2026
Integrated transcriptomic and proteomic profiling implicates prostaglandin-nitric oxide network dysregulation in uterine microcirculatory impairment in primary dysmenorrhea.
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Li Yufei, Yang Zongtong, Yu Beibei, Zhang Xinjun, Li Xiaojing, Chen Wenjing, Yuan Mengyu, Sui Zaiyun, Zhang Yue, Hou Wenjing, Gao Demin
Аннотация
BACKGROUND: Primary dysmenorrhea (PD) is a prevalent gynecological disorder characterized by severe menstrual pain. Although excessive prostaglandin activity is a recognized driver of uterine hypercontractility, the molecular mechanisms linking prostaglandin imbalance to nitric oxide (NO) deficiency, coagulation abnormalities, and impaired uterine microcirculation remain incompletely understood.
METHODS: A PD model was established in 12 female Sprague-Dawley rats (control, n = 6; PD, n = 6) using estradiol valerate, repeated cold exposure, and oxytocin stimulation. Behavioral testing, biochemical and hormonal assays, histopathological evaluation, coagulation analysis, uterine microcirculation assessment, integrated transcriptomic and proteomic analyses, and targeted measurement of arginine and proline were performed to characterize PD-associated alterations.
RESULTS: PD rats exhibited marked hyperalgesia, uterine hypercontractility, and reduced uterine blood perfusion. These changes were accompanied by significantly elevated uterine PGF2α and PGE2 levels, together with an increased PGF2α/PGE2 ratio (P < 0.01), indicating a shift toward a contractile and vasoconstrictive prostaglandin profile. PD rats also showed decreased plasma NO and β-endorphin (β-EP) levels, altered estradiol (E2) and progesterone (P) levels, uterine histopathological injury, and coagulation disturbance, consistent with impaired vascular regulation and endogenous analgesic capacity. Integrated transcriptomic and proteomic analyses revealed widespread molecular dysregulation in PD, with arginine and proline metabolism identified as the only pathway significantly enriched at both levels. Consistently, targeted measurement confirmed elevated uterine arginine and proline levels, suggesting a potential impairment in arginine utilization that may contribute to reduced NO bioavailability.
CONCLUSION: These findings support a systems-level model in which prostaglandin imbalance, coagulation-associated microcirculatory dysfunction, and dysregulated arginine-proline metabolism may jointly contribute to uterine ischemia and pain sensitization in PD. Our study proposes a refined molecular framework for PD pathogenesis and highlights the arginine-NO axis as a potential therapeutic target tworthy of future investigation.
METHODS: A PD model was established in 12 female Sprague-Dawley rats (control, n = 6; PD, n = 6) using estradiol valerate, repeated cold exposure, and oxytocin stimulation. Behavioral testing, biochemical and hormonal assays, histopathological evaluation, coagulation analysis, uterine microcirculation assessment, integrated transcriptomic and proteomic analyses, and targeted measurement of arginine and proline were performed to characterize PD-associated alterations.
RESULTS: PD rats exhibited marked hyperalgesia, uterine hypercontractility, and reduced uterine blood perfusion. These changes were accompanied by significantly elevated uterine PGF2α and PGE2 levels, together with an increased PGF2α/PGE2 ratio (P < 0.01), indicating a shift toward a contractile and vasoconstrictive prostaglandin profile. PD rats also showed decreased plasma NO and β-endorphin (β-EP) levels, altered estradiol (E2) and progesterone (P) levels, uterine histopathological injury, and coagulation disturbance, consistent with impaired vascular regulation and endogenous analgesic capacity. Integrated transcriptomic and proteomic analyses revealed widespread molecular dysregulation in PD, with arginine and proline metabolism identified as the only pathway significantly enriched at both levels. Consistently, targeted measurement confirmed elevated uterine arginine and proline levels, suggesting a potential impairment in arginine utilization that may contribute to reduced NO bioavailability.
CONCLUSION: These findings support a systems-level model in which prostaglandin imbalance, coagulation-associated microcirculatory dysfunction, and dysregulated arginine-proline metabolism may jointly contribute to uterine ischemia and pain sensitization in PD. Our study proposes a refined molecular framework for PD pathogenesis and highlights the arginine-NO axis as a potential therapeutic target tworthy of future investigation.