Maternal hypoxia activates endovascular trophoblast cell invasion

Abstract

Oxygen is a critical regulator of placentation. Early placental development occurs in a predominantly low oxygen environment and is, at least partially, under the control of hypoxia signaling pathways. In the present study, in vivo hypobaric hypoxia was used as an experimental tool to delineate hypoxia-sensitive events during placentation. Pregnant rats were exposed to the equivalent of 11% oxygen between days 6.5 and 13.5 of gestation. Pair-fed pregnant animals exposed to ambient conditions were included as a control group. Uterine mesometrial blood vessels in the hypoxia-exposed animals were greatly expanded and some contained large cuboidal cells that were positive for cytokeratin and other markers characteristic of invasive trophoblast cells. Unlike later in gestation, the route of trophoblast cell invasion in the hypoxia-exposed animals was restricted to endovascular, with no interstitial invasion observed. Hypoxia-activated endovascular trophoblast invasion required exposure to hypoxia from gestation day 8.5 to day 9.5. Activation of the invasive trophoblast lineage was also associated with an enlargement of the junctional zone of the chorioallantoic placenta, a source of invasive trophoblast cell progenitors. In summary, maternal hypoxia during early stages of placentation activates the invasive endovascular trophoblast cell lineage and promotes uterine vascular remodeling.

Natural killer cells direct hemochorial placentation by regulating hypoxia-inducible factor dependent trophoblast lineage decisions

“…1 L and M). The latter is restricted to the invasive trophoblast cell lineage (13,19). Similar effects of NK cell depletion on placentation were also observed in three additional inbred strains (F344, DSS, and BN; Fig.…”

“…Phenotypes of placentas with null mutations for several genes encoding components of the HIF signaling pathway exhibit failures in placentation (15,18). Exposure of pregnant rats to a hypoxic environment leads to alterations in placentation, especially expansion of the invasive trophoblast lineage (19). This is a conserved adaptive response.…”

NK cells, hypoxia and trophoblast cell differentiation

“…14 The effects of NK cell depletion on invasive trophoblast-directed uterine spiral artery remodeling can be mimicked by appropriately timed in vivo hypoxia exposure. 22 A critical developmental window of sensitivity to in vivo hypoxia exposure exists between E8.5 and E9.5 of rat pregnancy. This gestational interval represents a key developmental phase associated with commitment of trophoblast stem (TS)/precursor cells to differentiated trophoblast cell lineages of the junctional zone vs. the labyrinth zone.…”

“…In addition to the robust extension of endovascular trophoblast invasion deep into the uterine spiral arteries in both NK cell-depleted and maternal hypoxia in vivo models, the junctional zone also undergoes an expansion relative to the labyrinth zone. 14,22 TS cell populations are an excellent in vitro model system for elucidating mechanisms regulating differentiation. 23,24 TS cell exposure to a range of oxygen tensions can differentially influence cell proliferation and differentiation.…”

Trophoblast stem cells derived from nuclear transfer embryos: Phenotypically unique, bad neighbors, or poor communicators?

“…The junctional zone is expanded at the expense of the labyrinth zone, exhibiting prominent increases in the number of glycogen cells and size of spongiotrophoblast cells (4,16). Development of the junctional zone is particularly sensitive to the maternal environment (17,18). Thus, could there be impairments in the dialogue between maternal and trophoblast compartments, which lead to placentomegaly?…”