5 and E11.5 due to defects in placental vascularization, highlighting its role in placental vascular development [5]. Placentas of PPARγ-null mice are with an unsettled balance of pro- and anti-angiogenic factors, that is, increased proangiogenic factor proliferin and decreased anti-angiogenic factor proliferin-related protein.

This has been confirmed with “gain of function” studies because the PPARγ activator rosiglitazone Saracatinib manufacturer inhibits placental angiogenesis via regulating PRP and VEGF expression [90]. To this end, it is speculating that the critical PPARγ dimerization partner RXR may also have a role in placental angiogenesis because RXR-null mice show a similar phenotype to PPARγ [119]. Mammalian embryogenesis Mdm2 antagonist and placental development

are believed to take place under constant low-O2 relative to ambient O2 [54]. For example, in a human placenta the intervillous space O2 is as low as ~2% at ≤8–10 weeks of gestation at a time when placental vasculature forms; at the end of the first trimester this level rises threefold to ~8% when maternal blood is delivered into the placenta from the uterine spiral arteries; thereafter, O2 level gradually declines to ~6% at the end of the third trimester [102, 84], possibly due to the substantial increased demand of fetus. At the end of the third trimester, the O2 level in the human fetus is even lower, ~2.2% O2 (range 1.9–3.1%) and ~3.7% O2 (range 2.3–5.1%) in the umbilical artery and vein, respectively [102]. Low O2 or hypoxia is known to stimulate the expression of numerous hypoxia-responsive genes via HIF-1β, the also known as Arnt heterodimerization with

HIF-1α [32]. HIF-1β mediates hypoxia-induced transcription of many angiogenic genes in the placenta, including VEGF [41]. Thus, one would expect that HIF should play a critical role in placental angiogenesis. Surprisingly, vascular defect is likely to be secondary to the primary trophoblast defect in the Arnt-null mice [2]. This is because placentas of Arnt-null mice display greatly reduced size in the spongiotrophoblast and labyrinth layers but with increased numbers of giant trophoblast cells, suggesting that HIF-1β is critical for determining the fate of the trophoblasts [63]. The MAPK pathways are evolutionarily conserved signal transduction cascades that are implicated in control of different and even opposite cellular responses including proliferation, differentiation, and cell death. In vertebrates, multiple isoforms of MAPK have been identified and categorized into three subfamilies, that is, the ERKs, p38MAPK, and the JNKs or stress-activated protein kinases. The MAPK signaling is important for transmitting extracellular signals including growth factors, hormones, and chemokines into the intracellular targets for nearly all fundamental cellular processes. The p38MAPK comprises four members, including p38α/MAPK14, p38β/MAPK11, p38γ/MAPK12, and p38δ/MAPK13 [14].