Effects of Progesterone on iNOS, COX-2, and Collagen Expression in the Cervix
Stephen G. Marx , Melissa J. Wentz , Lynette B. MacKay , Dietmar Schlembach , Holger Maul , Cordula Fittkow , Randal Given , Yurij Vedernikov , George R. Saade and Robert E. Garfield *
* To whom correspondence should be addressed. E-mail: rgarfiel{at}utmb.edu.
Submitted on June 16, 2005
Accepted on 30 November 2005
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Abstract |
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The purpose of this study is to examine the relationship between iNOS and COX-2 in the control of cervical ripening and parturition under normal (normal term pregnancy) and abnormal (preterm labor and the prolongation of pregnancy) conditions. This is accomplished by (1) measuring changes in the collagen both visually and quantitatively; (2) by localizing and characterizing iNOS and COX-2 under normal conditions; and (3) by characterizing the changes in the iNOS and COX-2 expression under abnormal conditions. Cervices are obtained from estrus and timed pregnant Sprague-Dawley rats (n=4-10 per group). Preterm labor is induced with Onapristone (3 mg/rat; progesterone antagonist) and the prolongation of pregnancy with progesterone (2.5 mg, twice daily). Collagen changes are measured and visualized with the picrosirius polarization method. RT-PCR is utilized to characterize the mRNA expression (p<0.05), and immunohistochemistry is utilized to localize the protein expression for the iNOS and COX-2. The organization and birefringence of the collagen during pregnancy decreased and is supported by changes in the luminosity (p<0.001). The iNOS and COX-2 enzymes were localized in the cervical smooth muscle, vascular smooth muscle, and epithelium. Under normal conditions, iNOS mRNA levels decreased as COX-2 mRNA levels increased demonstrating an inverse correlation (Spearman r = -0.497; p = 0.00295). Onapristone stimulated preterm labor, increasing the iNOS and COX-2 mRNA (p<0.05). The increase demonstrated a positive correlation (Spearman r = 0.456; p = 0.03). Progesterone prolonged pregnancy, decreasing the iNOS and COX-2 mRNA (p = 0.036). In conclusion, there may be an interaction between the NO and PG pathways in cervical ripening and parturition.
Key Words:
iNOS, COX-2, rat, cervix, progesterone, Onapristone, cervical ripening, parturition, nitric oxide, prostaglandin
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