title: Effects of reduced maternal lipoprotein-cholesterol availability on placental progesterone biosynthesis in the baboon.
abstract: Maternal low density lipoprotein (LDL) is the principal source of cholesterol substrate for progesterone biosynthesis in the primate placental syncytiotrophoblast. The relationship of LDL-cholesterol availability and other potential cholesterol-yielding pathways to placental progesterone production have not, however, been demonstrated in vivo in a nonhuman primate. Therefore, maternal peripheral lipoprotein-cholesterol and progesterone concentrations were determined in blood samples obtained by venipuncture, from day 72 until day 100, from pregnant baboons (Papio sp) that were either untreated (n = 4) or treated (n = 3) with the inhibitor of hepatic lipoprotein production, 4-aminopyrazolo [3-4-d]pyrimidine (4-APP, 10 mg/kg BW) on days 98-99 of pregnancy (term = 184 days). Although LDL-cholesterol and progesterone levels remained unchanged in untreated animals, LDL-cholesterol concentrations were 9-fold lower (P < 0.005) in baboons receiving 4-APP than in untreated baboons 2 days following initial administration. Commensurate progesterone levels were 3.5-fold lower (P < 0.03) in 4-APP-treated baboons than in untreated baboons. RT-PCR was used to approximate relative changes in transcription of messengers RNAs (mRNAs) for selected cholesterol-sensitive pathways in placental tissue collected on day 100. Thus, expression of mRNAs for LDL receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase appeared enhanced, whereas acyl-coenzyme A:cholesterol acyl transferase (ACAT) mRNA was diminished in syncytiotrophoblast-enriched cell fractions as a result of 4-APP administration. No relative differences in mRNAs were apparent in whole placental villous tissue, however, as a result of 4-APP treatment. In summary, this experiment demonstrates a significant decline in progesterone production elicited by maternal LDL-cholesterol withdrawal, and attests to the efficacy of 4-APP administration during baboon pregnancy. These results also suggest a commensurate regulation of cholesterol-sensitive pathways in primate syncytiotrophoblast. However, no relative differences were apparent in mRNA levels for LDL receptor, HMG-CoA and ACAT in whole placental villous tissue as a result of LDL-cholesterol withdrawal, which may suggest potential disparities in the mechanisms regulating cholesterol homeostasis in steroidogenically active syncytiotrophoblasts vs. those in proliferative nonendocrine placental constituents.
authors.affiliation: Department of Obstetrics/Gynecology, Tulane University School of Medicine, New Orleans, Louisiana 70112-2699, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Henson
authors.forename: S J
authors.initials: SJ
authors.lastname: Greene
authors.forename: B C
authors.initials: BC
authors.lastname: Reggio
authors.forename: W
authors.initials: W
authors.lastname: Shi
authors.forename: K F
authors.initials: KF
authors.lastname: Swan
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D008078:Cholesterol, LDL / Q000378:metabolism*; D005260:Female; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D010215:Papio; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011374:Progesterone / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D014327:Trophoblasts / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D012333:RNA, Messenger; D011973:Receptors, LDL; C004420:4-aminopyrazolo(3,4-d)pyrimidine; D011374:Progesterone; D006903:Hydroxymethylglutaryl CoA Reductases; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D002785:Sterol O-Acyltransferase; D000225:Adenine