Effects of parathyroid hormone like hormone (PTHLH) antagonist, PTHLH(7-34), on fetoplacental development and growth during midgestation in rats.
Parathyroid hormone-like hormone (PTHLH) secretion has been reported in human amnion, chorion, decidual cytotrophoblast, syncytiotrophoblast, endometrium, and myometrium; however, the functions of PTHLH during pregnancy, particularly during placenta formation and fetal development, are not well understood. We examined whether neutralization of PTHLH action using PTHLH antagonist, PTHLH(7-34), in rats during early gestation affects fetal and placental growth. Rats received s.c. a daily dose of either 0, 4, 12, or 36 microg of PTHLH(7-34) infused continuously through mini-osmotic pumps from Day 8 through Day 15 of pregnancy. Fetal weights measured on Day 15 were significantly decreased in rats treated with all the doses of PTHLH(7-34) compared to controls, and decreases in placental weights were significant at the 12-microg dose. TUNEL assay demonstrated an increased number of apoptotic cells in placenta of treated rats, including rats treated with the 4-microg dose. Cleaved caspase 3 (CASP3), caspase 9 (CASP9) (P < 0.05) and poly-ADP-ribose polymerase (PARP1) (P < 0.01) expression was increased and BCL2 (P < 0.01) expression was decreased in rats treated with 4 microg PTHLH(7-34) compared to that in control. Placental cytochrome c expression was increased (P < 0.01) in cytosolic and decreased (P < 0.01) in mitochondrial fraction in PTHLH(7-34)-treated rats. Caspase 8 expression was not affected by the treatment. Immunohistochemical analysis of platelet endothelial cell adhesion molecule (PECAM1) showed higher staining intensity in control than in treated rats. In conclusion, these results suggests that PTHLH plays a role in early pregnancy, and that antagonization of PTHLH action causes fetoplacental growth restriction through activation of mitochondrial pathway of apoptosis in the placenta and through decreased expression of PECAM1.
Thota
C S
CS
Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas 77555-1062, USA.
Reed
L C
LC
Yallampalli
C
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins; D053181:Caspase 8; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D045304:Cytochromes c / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D005865:Gestational Age; D006727:Hormone Antagonists / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D044162:Parathyroid Hormone-Related Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D010920:Placenta / Q000187:drug effects*; D010929:Placentation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000187:drug effects
D051017:Apoptosis Regulatory Proteins; C494774:Bak1 protein, rat; D053468:CARD Signaling Adaptor Proteins; C498975:Card10 protein, mouse; D006727:Hormone Antagonists; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D045304:Cytochromes c; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse; C505528:Casp8 protein, rat; D053181:Caspase 8; D020169:Caspases