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.
Highlights
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The placental-phenotype of this disease is largely attributed to vascular dysfunction of the placenta, the organ in other tissues, how pericytes contribute to vascular growth and signaling that serves as the master regulator of in the placenta remains unknown
Reduced vascular perfusion, increased oxidative stress, increased neutrophil recruitment, and an altered angiogenic response have all been observed in clinical presentations pericytes are shown to contribute to growth restriction of microvessels over of this disease; the exact cause time, an effect that is strongly regulated by vascular endothelial growth factor and Angiopoietin/Tie2 signaling
Summary
No models of perfusable placental microvasculature exist—yet these are necessary to explore the role of stromal cells in placental vascular dysfunction. Considering the prominence of VEGFA and bFGF in early vascular development (in particular of mesenchymal villi) and their deficit in PE,[31] both proangiogenic (vessel forming) cytokines were employed exogenously in an effort to promote microvessel growth and maintenance in HPP-HUVEC cocultures While these growth factors (GFs) improved vascular growth for HPPs in the initial days following seeding, their effect was insufficient for generating connected vasculature and resulted in a decreased connectivity ratio over time (Figure 2e). While we cannot recapitulate all aspects of placental microvasculature, the features of our model allows us to study key signaling pathways and vessel function in more detail to understand what events may be dysregulated in placental vasculopathies, such as those seen in PE
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