Chronic estrogen deficiency causes gastroparesis by altering neuronal nitric oxide synthase function

Area of Science:

• Gastroenterology and Endocrinology
• Molecular and Cellular Biology
• Reproductive Biology

Background:

• Gastroparesis disproportionately affects females, yet the underlying biological reasons remain unknown.
• Nitric oxide synthase (nNOS)-dependent gastric motility is impaired in diabetic gastroparesis, with evidence suggesting nNOS is regulated by estrogen.

Purpose of the Study:

• To investigate if reduced estradiol-17β (E2) levels down-regulate tetrahydrobiopterin (BH4) biosynthesis, leading to impaired nNOS-mediated gastric motility.
• To examine these effects in follicle stimulating hormone receptor knock-out (FORKO) female mice, a model of chronic estrogen deficiency.

Main Methods:

• Gastric emptying and nitrergic relaxation were measured in female FORKO and wild-type (WT) mice.
• Protein expression of nNOSα, BH4 biosynthesis enzymes (GCH-1, DHFR), and estrogen receptors (ERα, ERβ) were analyzed via Western blotting.
• Biopterin levels (BH4, BH2, B) were quantified using High-Performance Liquid Chromatography (HPLC).

Main Results:

• FORKO mice exhibited reduced gastric emptying and impaired nitrergic relaxation compared to WT mice.
• Decreased nitric oxide (NO) release and reduced expression of GCH-1, DHFR, and ERα were observed in FORKO mice.
• Increased nNOS dimerization and elevated oxidized biopterin levels with a decreased BH4/BH2+B ratio were identified in FORKO mice.

Conclusions:

• Chronic estrogen deficiency negatively impacts both BH4 and nNOS function.
• These molecular alterations contribute to the development of gastroparesis in the FORKO mouse model.
• The findings suggest a potential mechanism for the gender bias observed in gastroparesis.