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

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.

Zika Virus Infects Human Placental Mast Cells and the HMC-1 Cell Line, and Triggers Degranulation, Cytokine Release and Ultrastructural Changes

“…In support of our findings, an increase in cytokines related to the inflammatory environment in placental ZIKV infection has already been observed in another study performed by our group, with an increase in TNF-α and the VEGFR-2 receptor [28]. TNF-α combined with VEGF were similarly related to vascular placental dysfunction, leading to plasma overflow and preeclampsia [47]. The stabilization of mast cells can decrease their response and minimize the severity in dengue, which is related to the release of VEGF and vascular permeability [48].…”

Glycocalyx-Mediated Vascular Dissemination of Circulating Tumor Cells

“…1b), consistent with the idea 50 that the EC GCX can sterically hinder passage of macromolecules 32 . Indeed, this increase in 51 permeability was not likely due to disrupted endothelial cell-cell junctions since ZO-1 localization 52 revealed no visible changes in tight junction morphology, and treatment with the pro-inflammatory 53 factor TNF-α, known to disrupt both the EC GCX and EC junctions 33,34 , produced a much larger 6.9- 54 fold increase in permeability (not shown). Thus, it is likely that the increase in permeability observed 55 stemmed from increased diffusion of dextran across the degraded GCX layer between ECs through 56 depletion of its solid, charged fraction, thereby increasing the GCX inter-fiber spacing and mean free 57 path of the molecules 35,36 .…”

“…The MVNs possess 32 morphological similarities to the human microvasculature in vivo and express a functional GCX 29 . 33 Perfusion of tumor cells in the MVNs can be used to quantify TC extravasation events 30 . Using MVNs, 34 we dissect the process of TCs dissemination into arrest, adhesion, and trans-endothelial migration, 35 and find that the GCX plays unexpected key roles in all of these processes ultimately leading to 36 metastasis.…”

Perivascular Secretome Influences Hematopoietic Stem Cell Maintenance in a Gelatin Hydrogel

“…43 More recently, we showed 20 paracrine signals from marrow-derived mesenchymal stem cells could enhance the retention of quiescent HSCs, 26 though this effect was also strongly dependent on the relative ratio of HSCs to MSCs as well as on processes of MSC-mediated hydrogel remodeling. Separately, a wide range of studies have focused on developing microphysiological models of the perivascular environment to interrogate processes associated with disease progression, 9,29,54,55 cancer invasion or metastasis, 4,37,50,51,66 and even dormancy of cancer stem cells. 10,24 These studies provide an illustrative example of the power of the perivascular environment and motivate our study of the role of perivascular signals on murine HSC culture.…”