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Altered gene expression profile in ovarian follicle in rats treated with indomethacin and RU486
Kenjiro Tsubota1, Masayuki Kanki, Takahisa Noto
1Drug Safety Research Laboratories, Astellas Pharma Inc.
Abstract:
It is well-known that indomethacin (the cyclooxygenase 1 & 2 inhibitor) and RU486 (or mifepristone, the progesterone receptor antagonist) block follicular rupture in rats. To characterize genetic alterations in unruptured follicles, gene expression profiles in ovarian follicle were analyzed in indomethacin- and RU486-treated female Sprague-Dawley rats. Ovaries are collected at 22:00 on the proestrus day and 10:00 on the following estrus day after a single dose of indomethacin and RU486. Histopathologically, changes depicting responses to LH surge were observed in ovaries, uteri and vagina. Total RNA was extracted from pre-ovulatory follicles or unruptured follicles collected by laser microdissection and analyzed by Genechip(®). Among genes showing statistically significant changes compared to control groups, following changes were considered relevant to induction of unruptured follicles. In indomethacin-treated rats, Wnt4 was down-regulated, suggesting effect on tissue integrity and steroid genesis. In RU486-treated rats, Adamts1, Adamts9, Edn2, Ednra, Lyve1, Plat, and Pparg were down-regulated. These changes suggest effects on proteolysis for extra cellular matrix or surrounding tissue (Adamts1 & 9, and Plat), constriction of smooth muscle surrounding follicles (Edn2, Ednra, and Pparg), follicular fluid (Lyve1), and angiogenesis (Pparg). Down-regulation of angiogenesis related genes (Angpt2, Hmox1, and Vegfa) was observed in both treatment groups. Here, we clarify genetic alterations induced by the inhibition of cyclooxygenase or progesterone receptor.
Insights
Indomethacin and RU486 treatment in rats blocked follicular rupture, altering gene expression. Key genes involved in tissue integrity, proteolysis, smooth muscle constriction, and angiogenesis were affected, clarifying genetic changes in unruptured follicles.
Area of Science:
- Reproductive biology and molecular genetics.
Background:
- Indomethacin (cyclooxygenase inhibitor) and RU486 (progesterone receptor antagonist) are known to inhibit follicular rupture in rats.
- Understanding the genetic mechanisms behind this blockage is crucial for reproductive research.
Purpose of the Study:
- To characterize the genetic alterations occurring in unruptured ovarian follicles following treatment with indomethacin or RU486.
- To identify specific genes and pathways affected by the inhibition of cyclooxygenase or progesterone receptor.
Main Methods:
- Gene expression profiling of ovarian follicles from Sprague-Dawley rats treated with indomethacin or RU486.
- Ovaries were collected on proestrus and estrus days.
- Laser microdissection was used to isolate pre-ovulatory and unruptured follicles for RNA extraction and Genechip analysis.
Main Results:
- Indomethacin treatment led to down-regulation of Wnt4, impacting tissue integrity and steroidogenesis.
- RU486 treatment resulted in down-regulation of genes involved in proteolysis (Adamts1, Adamts9, Plat), smooth muscle constriction (Edn2, Ednra, Pparg), follicular fluid (Lyve1), and angiogenesis (Pparg).
- Both treatments showed down-regulation of angiogenesis-related genes (Angpt2, Hmox1, Vegfa).
Conclusions:
- Inhibition of cyclooxygenase or progesterone receptor induces specific genetic changes in ovarian follicles.
- These alterations affect critical processes including extracellular matrix remodeling, smooth muscle function, and angiogenesis, leading to the formation of unruptured follicles.
