Effects of progesterone on iNOS, COX-2, and collagen expression in the cervix.
This study examines the relationship between inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the control of cervical ripening and parturition under normal (normal term pregnancy) and abnormal (preterm labor and prolongation of pregnancy) conditions by (a) measuring changes in the collagen both visually and quantitatively, (b) localizing and characterizing iNOS and COX-2 under normal conditions, and (c) characterizing the changes in iNOS and COX-2 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 used to characterize the mRNA expression (p<0.05), and immunohistochemistry is used to localize the protein expression for 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 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 nitric oxide and prostaglandin pathways in cervical ripening and parturition.
Marx
Stephen G
SG
The University of Texas Medical Branch, Department of Obstetrics and Gynecology, Medical Research Bldg. 11.104, 301 University Boulevard, Galveston, Texas 77555-106, USA.
Wentz
Melissa J
MJ
Mackay
Lynette B
LB
Schlembach
Dietmar
D
Maul
Holger
H
Fittkow
Cordula
C
Given
Randal
R
Vedernikov
Yurij
Y
Saade
George R
GR
Garfield
Robert E
RE
D000818:Animals; D001391:Azo Compounds; D020070:Cervical Ripening / Q000187:drug effects / Q000378:metabolism; D002584:Cervix Uteri / Q000187:drug effects* / Q000378:metabolism; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics; D004396:Coloring Agents; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D006067:Gonanes / Q000494:pharmacology; D007150:Immunohistochemistry; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000235:genetics; D007752:Obstetric Labor, Premature / Q000139:chemically induced / Q000378:metabolism; D009928:Organ Specificity; D036801:Parturition / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D011273:Pregnancy, Prolonged / Q000139:chemically induced / Q000378:metabolism; D011374:Progesterone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001391:Azo Compounds; D004396:Coloring Agents; D006067:Gonanes; D012333:RNA, Messenger; C009798:C.I. direct red 80; D011374:Progesterone; D003094:Collagen; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; C053238:onapristone