Genome-wide expression profiling of placentas in the p57Kip2 model of pre-eclampsia.
Pre-eclampsia affects 6-10% of pregnancies and is one of the primary causes of premature birth. It is widely accepted that inappropriate placental development, combined with environmental factors, plays a major role in disease pathogenesis. The p57(Kip2) mouse is the only mouse model of pre-eclampsia that recapitulates the full spectrum of symptoms of the human disease, including placental abnormalities, hypertension, proteinuria and premature labour. In addition, pregnant females expressing wild-type levels of p57(Kip2) develop pre-eclampsia when carrying fetuses that lack p57(Kip2) expression. This demonstrates that either the fetus or the placenta causes the disease. Here, taking advantage of the unique genetics of the p57(Kip2) mouse, we have used full genome expression profiling to define the placental aspect of the p57(Kip2) phenotype at a molecular level and to conduct an unbiased search for factors involved in pre-eclampsia pathogenesis. During this analysis, we found that although mutant embryos demonstrate altered placental architecture and have histological changes indicative of reduced utero-placental blood flow, the p57(Kip2) pregnant females do not demonstrate hypertension or renal pathology. This suggests a model in which placental abnormalities cause pre-eclampsia only given other environmental variables. On the basis of this model, we expect that misregulation of molecular factors, while not able to cause a full spectrum of disease symptoms in this context, still occurs in these p57(Kip2) mutant mice. Our studies suggest a role for environmental factors in the p57(Kip2) pre-eclampsia phenotype and have identified several candidates for pre-eclampsia predisposition in this model, including known regulators of blood pressure, inflammation and apoptosis.
Knox
K S
KS
Genetics Department, Standford University, Stanford, CA 94062, USA.
Baker
J C
JC
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001794:Blood Pressure / Q000235:genetics; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D005838:Genotype; D006728:Hormones / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D010920:Placenta / Q000378:metabolism* / Q000473:pathology; D011225:Pre-Eclampsia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism
C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D006728:Hormones; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1