PPARgamma in placental angiogenesis.
Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor involved in diverse biological processes including adipocyte differentiation, glucose homeostasis, and inflammatory responses. Analyses of PPARγ knockout animals have been so far preempted by the early embryonic death of PPARγ-/- embryos as a consequence of the severe alteration of their placental vasculature. Using Sox2Cre/PPARγL2/L2 mice, we obtained fully viable PPARγ-null mice through specific and total epiblastic gene deletion, thereby demonstrating that the placental defect is the unique cause of PPARγ-/- embryonic lethality. The vasculature defects observed in PPARγ-/- placentas at embryonic d 9.5 correlated with an unsettled balance of pro- and antiangiogenic factors as demonstrated by increased levels of proliferin (Prl2c2, PLF) and decreased levels of proliferin-related protein (Prl7d1, PRP), respectively. To analyze the role of PPARγ in the later stage of placental development, when its expression peaks, we treated pregnant wild-type mice with the PPARγ agonist rosiglitazone. This treatment resulted in a disorganization of the placental layers and an altered placental microvasculature, accompanied by the decreased expression of proangiogenic genes such as Prl2c2, vascular endothelial growth factor, and Pecam1. Together our data demonstrate that PPARγ plays a pivotal role in controlling placental vascular proliferation and contributes to its termination in late pregnancy.
Nadra
Karim
K
Center for Integrative Genomics, Department of Medical Genetics and Electron Microscopy Platform, University of Lausanne, CH-1015 Lausanne, Switzerland.
Quignodon
Laure
L
Sardella
Chiara
C
Joye
Elisabeth
E
Mucciolo
Antonio
A
Chrast
Roman
R
Desvergne
Béatrice
B
D000818:Animals; D020964:Embryo Loss / Q000235:genetics / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D005855:Germ Layers / Q000378:metabolism; D005865:Gestational Age; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000235:genetics*; D009928:Organ Specificity / Q000235:genetics; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010920:Placenta / Q000098:blood supply* / Q000378:metabolism; D011247:Pregnancy; D011388:Prolactin; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
D006023:Glycoproteins; D007004:Hypoglycemic Agents; D036341:Intercellular Signaling Peptides and Proteins; D047495:PPAR gamma; C000634106:Prl2c2 protein, mouse; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D011388:Prolactin