Pericytes Contribute to Dysfunction in a Human 3D Model of Placental Microvasculature through VEGF-Ang-Tie2 Signaling
Pericytes Contribute to Dysfunction in a Human 3D Model of Placental Microvasculature through VEGF-Ang-Tie2 Signaling
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DOI：
10.1002/advs.201900878
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发表时间：
2019-10-29
期刊：
影响因子：
15.1
通讯作者：
Kamm, Roger D.
中科院分区：
文献类型：
--
作者：
Haase, Kristina;Gillrie, Mark R.;Kamm, Roger D.
胎盘血管病变与许多妊娠相关疾病有关，包括先兆子痫（PE），这是全世界孕产妇-胎儿发病率和死亡率的主要原因。胎盘PE的表现与内皮功能障碍、血管灌注减少、白细胞浸润和胎盘内血管生成因子的改变（一种候选机制）有关。尽管在其他组织中维持血管静止，但周细胞如何促进胎盘中的血管生长和信号传导仍不清楚。这里，周细胞被假设在胎盘血管生长的发病机制中起着有害的作用。建立了一个可灌注的三培养模型，由人内皮细胞、成纤维细胞和周细胞组成，能够在模拟胎盘微血管炎症的系统中重现生长和重塑。随着时间的推移，胎盘周细胞有助于微血管的生长限制，这一作用受到血管内皮生长因子和血管生成素/Tie2信号的强烈调节。此外，该模型能够概括基本过程，包括肿瘤坏死因子α (TNF α)介导的血管渗漏和白细胞浸润，这两个重要方面都与胎盘PE相关。这个胎盘血管模型强调了内皮-周细胞串扰的不平衡在血管病理和相关疾病的发展中起着关键作用。
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 (TNF alpha)-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.