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      Pericytes Contribute to Dysfunction in a Human 3D Model of Placental Microvasculature through VEGF‐Ang‐Tie2 Signaling

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          Abstract

          Placental vasculopathies are associated with a number of pregnancy‐related diseases, including pre‐eclampsia (PE)—a leading cause of maternal–fetal morbidity and mortality worldwide. Placental presentations of PE are associated with endothelial dysfunction, reduced vessel perfusion, white blood cell infiltration, and altered production of angiogenic factors within the placenta (a candidate mechanism). Despite maintaining vascular quiescence in other tissues, how pericytes contribute to vascular growth and signaling in the placenta remains unknown. Here, pericytes are hypothesized to play a detrimental role in the pathogenesis of placental vascular growth. A perfusable triculture model is developed, consisting of human endothelial cells, fibroblasts, and pericytes, capable of recapitulating growth and remodeling in a system that mimics inflamed placental microvessels. Placental pericytes are shown to contribute to growth restriction of microvessels over time, an effect that is strongly regulated by vascular endothelial growth factor and Angiopoietin/Tie2 signaling. Furthermore, this model is capable of recapitulating essential processes including tumor necrosis factor alpha (TNFα)‐mediated vascular leakage and leukocyte infiltration, both important aspects associated with placental PE. This placental vascular model highlights that an imbalance in endothelial–pericyte crosstalk can play a critical role in the development of vascular pathology and associated diseases.

          Abstract

          A model of perfusable placental microvasculature recapitulates vessel remodeling in 3D, altered barrier function, and infiltration by polymorphonuclear neutrophils—key observations associated with placental vasculopathies, such as those often present in pre‐eclampsia. Here, endothelial–pericyte interactions significantly impact vessel remodeling, with pericytes causing growth restriction—a process regulated by vascular endothelial growth factor and the Ang/Tie2 signaling axis.

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          Author and article information

          Contributors
          kristina.haase@embl.es
          rdkamm@mit.edu
          Journal
          Adv Sci (Weinh)
          Adv Sci (Weinh)
          10.1002/(ISSN)2198-3844
          ADVS
          Advanced Science
          John Wiley and Sons Inc. (Hoboken )
          2198-3844
          29 October 2019
          December 2019
          : 6
          : 23 ( doiID: 10.1002/advs.v6.23 )
          : 1900878
          Affiliations
          [ 1 ] Massachusetts Institute of Technology Cambridge MA 02139 USA
          [ 2 ] Department of Medicine University of Calgary Calgary AB T2N 1N4 Canada
          [ 3 ]Present address: EMBL Barcelona Carrer del Dr. Aiguader, 88 Barcelona Spain 08003
          Author notes
          Author information
          https://orcid.org/0000-0002-7232-304X
          Article
          ADVS1395
          10.1002/advs.201900878
          6891921
          31832308
          33aae142-7555-44fb-b39f-34d62cf0cc74
          © 2019 The Authors. Published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim

          This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

          History
          : 23 April 2019
          : 18 September 2019
          Page count
          Figures: 8, Tables: 0, Pages: 14, Words: 8929
          Funding
          Funded by: NSERC , open-funder-registry 10.13039/501100000038;
          Funded by: National Science Foundation , open-funder-registry 10.13039/100000001;
          Award ID: CBET‐0939511
          Funded by: Canadian Institutes of Health Research , open-funder-registry 10.13039/501100000024;
          Funded by: National Science Foundation , open-funder-registry 10.13039/100000001;
          Award ID: CBET‐0939511
          Categories
          Full Paper
          Full Papers
          Custom metadata
          2.0
          December 4, 2019
          Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.2 mode:remove_FC converted:04.12.2019

          angiogenesis,pericytes,placenta,pre‐eclampsia,vascular dysfunction

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