Goeckel Megan E, Lee Jihui, Levitas Allison, Colijn Sarah, Mun Geonyoung, Burton Zarek, Chintalapati Bharadwaj, Yin Ying, Abello Javier, Stratman Amber
Department of Cell Biology and Physiology, Washington University School of Medicine St. Louis, MO, 63110.
University of Nebraska Medical Center, Graduate Studies, Nebraska Medical Center, Omaha, NE 68198.
bioRxiv. 2023 Sep 17:2023.09.16.557842. doi: 10.1101/2023.09.16.557842.
Endothelial cell (EC)-pericyte interactions are known to remodel in response to hemodynamic forces, yet there is a lack of mechanistic understanding of the signaling pathways that underlie these events. Here, we have identified a novel signaling network regulated by blood flow in ECs-the chemokine receptor, CXCR3, and one of its ligands, CXCL11-that delimits EC angiogenic potential and suppresses pericyte recruitment during development through regulation of expression in ECs. modeling of EC-pericyte interactions demonstrates that suppression of EC-specific CXCR3 signaling leads to loss of pericyte association with EC tubes. , phenotypic defects are particularly noted in the cranial vasculature, where we see a loss of pericyte association with and expansion of the vasculature in zebrafish treated with the Cxcr3 inhibitor AMG487. We also demonstrate using flow modeling platforms that CXCR3-deficient ECs are more elongated, move more slowly, and have impaired EC-EC junctions compared to their control counterparts. Together these data suggest that CXCR3 signaling in ECs drives vascular stabilization events during development.
已知内皮细胞（EC）与周细胞之间的相互作用会因血流动力学力而重塑，但对于这些事件背后的信号通路缺乏机制上的理解。在此，我们确定了一种由内皮细胞中的血流调节的新型信号网络——趋化因子受体CXCR3及其配体之一CXCL11——其通过调节内皮细胞中的表达来界定内皮细胞的血管生成潜力，并在发育过程中抑制周细胞募集。内皮细胞与周细胞相互作用的建模表明，抑制内皮细胞特异性CXCR3信号会导致周细胞与内皮细胞管的结合丧失。此外，在颅脑血管系统中特别注意到表型缺陷，在用Cxcr3抑制剂AMG487处理的斑马鱼中，我们看到周细胞与血管的结合丧失以及血管扩张。我们还使用血流建模平台证明，与对照对应物相比，缺乏CXCR3的内皮细胞更细长，移动更慢，并且内皮细胞 - 内皮细胞连接受损。这些数据共同表明，内皮细胞中的CXCR3信号在发育过程中驱动血管稳定事件。
