Disruption of oxygen-regulated responses underlies pathological changes in the placentas of women who smoke or who are passively exposed to smoke during pregnancy.
Previously, we showed that maternal smoking harms human placental development by changing the balance between cytotrophoblast (CTB) proliferation and differentiation. To understand the mechanisms involved, we studied the effects of maternal smoking and in vitro exposure of CTBs to nicotine and on CTB expression of molecules that govern cellular responses to oxygen tension: the von Hippel-Lindau tumor suppressor protein (pVHL), the hypoxia-inducible transcription factors (HIFs), and the vascular endothelial growth factors (VEGFs). We previously reported that hypoxia upregulates CTB pVHL expression (1). Here we show that in vitro exposure of CTBs to nicotine has the same effect. Maternal smoking also dysregulated CTB expression of all three molecules. Remarkably, we found that passive exposure to cigarette smoke had many of the same effects as active smoking, a graphic demonstration of the ill effects of cigarette smoke, even secondhand, on placental development. Together, these findings explain, in part, how smoking damages the placenta by altering expression of key mediators of placental development.
Genbacev
Olga
O
Department of Stomatology, University of California San Francisco, San Francisco, CA 94143-0512, USA.
McMaster
Michael T
MT
Zdravkovic
Tamara
T
Fisher
Susan J
SJ
D000028:Abortion, Induced; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D002824:Chorionic Villi / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D007797:Laminin / Q000378:metabolism; D016253:Microscopy, Immunoelectron; D008954:Models, Biological; D009538:Nicotine / Q000009:adverse effects / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism*; D010920:Placenta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011509:Proteoglycans / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D044767:Ubiquitin-Protein Ligases / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D000911:Antibodies, Monoclonal; D004338:Drug Combinations; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007797:Laminin; D011509:Proteoglycans; D014028:Tobacco Smoke Pollution; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D009538:Nicotine; D003094:Collagen; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human; D010100:Oxygen