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. 2018 Aug 24;13(8):e0202648.
doi: 10.1371/journal.pone.0202648. eCollection 2018.

The Direct and Sustained Consequences of Severe Placental Hypoxia on Vascular Contractility

Free PMC article

The Direct and Sustained Consequences of Severe Placental Hypoxia on Vascular Contractility

Philippe Vangrieken et al. PLoS One. .
Free PMC article


Introduction: Preeclampsia is a major health problem in human pregnancy, severely complicating 5-8% of all pregnancies. The emerging molecular mechanism is that conditions like hypoxic stress trigger the release of placental messengers into the maternal circulation, which causes preeclampsia. Our objective was to develop an in vitro model, which can be used to further elucidate the molecular mechanisms of preeclampsia and which might be used to find a remedy.

Methods: Human non-complicated term placentas were collected. Placental explants were subjected to severe hypoxia and the conditioned media were added to chorionic arteries that were mounted into a myograph. Contractile responses of the conditioned media were determined, as well as effects on thromboxane-A2 (U46619) induced contractility. To identify the vasoactive compounds present in the conditioned media, specific receptor antagonists were evaluated.

Results: Factors released by placental explants generated under severe hypoxia induced an increased vasoconstriction and vascular contractility to thromboxane-A2. It was found that agonists for the angiotensin-I and endothelin-1 receptor released by placental tissue under severe hypoxia provoke vasoconstriction. The dietary antioxidant quercetin could partially prevent the acute and sustained vascular effects in a concentration-dependent manner.

Discussion: Both the acute vasoconstriction, as well as the increased contractility to U46619 are in line with the clinical vascular complications observed in preeclampsia. Data obtained with quercetin supports that our model opens avenues for e.g. nutritional interventions aimed at treating or preventing preeclampsia.

Conflict of interest statement

The authors have declared that no competing interests exist.


Fig 1
Fig 1. In vitro model for severe placental hypoxia and testing the vascular effect of PSMs.
Schematic overview of the In vitro model for PE where placental explants are exposed to severe hypoxia and PSMs are tested on chorionic arteries. Differences in contractile response are used as read-out (A) and a schematic overview for measuring the acute (ΔI) and sustained (ΔII) vascular effect of PSMs (B).
Fig 2
Fig 2. Vasodilation of chorionic arteries.
Concentration-dependent relaxation of placental chorionic arteries induced by ACh (n = 6) (A), BK (n = 3) (B), Car (n = 3) (C) or SNP (n = 5) (D), after a pre-contraction induced by KCl 65.5 mM, except for BK, which was after a pre-contraction by U46619 (n = 4) (E).
Fig 3
Fig 3. Vasoconstriction of chorionic arteries.
Concentration-dependent contractions of placental chorionic arteries induced by U46619 (n = 3) (A), AngII (n = 3) (B), ET-1 (n = 4) (C), or 5-HT (n = 6) (D), compared to a pre-contraction induced by KCl 65.5 mM.
Fig 4
Fig 4. Vasoactive responses of chorionic arteries to PSMs.
The vascular contractile response over time (60 min) induced by PSMs released during exposure to room air (control) (n = 8) or hypoxia (n = 8) (A). The maximum response after 60 min (n = 8) (B) and differences in vascular contractility to U46619 before and after exposure to PSMs for both conditions (n = 8) (C).
Fig 5
Fig 5. Characterization of vasoactive PSMs released under hypoxia.
The vascular contractile response over time (60 min) induced by PSMs released under hypoxia in combination with a 15 min pre-incubation with either 30 μM Bos (n = 3) (A), or 30 μM Ket (n = 3) (B), or 30 μM Los (n = 3) (C), or 30 μM Bos + Los (n = 3) (D). The maximum response to PSMs released under hypoxia after 60 min (n = 3) (E).
Fig 6
Fig 6. Effects of quercetin on the release of PSMs under hypoxia.
The maximum vascular contractile response after 60 min induced by PSMs released under hypoxia (control) (n = 27), hypoxia in combination with 0.3, 1, 3, 10 or 20 μM quercetin (n = 8) (A) and the difference in vascular contractility to U46619 before and after exposure to the PSMs for each condition (B).

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Grant support

This study was funded by the internal source: “Nutrim Graduate Programme” and supported by the external source: “Fonds gezond geboren” (PV). There was no additional external funding received for this study.