Vascular endothelial cells (vECs) in the brain exhibit structural and functional heterogeneity. Fenestrated, permeable brain vasculature mediates neuroendocrine function, body-fluid regulation, and neural immune responses, however its vascular formation remains poorly understood. Here we show that specific combinations of vascular endothelial growth factors (Vegfs) are required to selectively drive fenestrated vessel formation in the zebrafish myelencephalic choroid plexus (mCP). We found that the combined, but not individual, loss of Vegfab, Vegfc, and Vegfd causes severely impaired mCP vascularization with little effect on neighboring non-fenestrated brain vessel formation, demonstrating fenestrated-vEC-specific angiogenic requirements. This Vegfs-mediated vessel-selective patterning also involves Ccbe1. Expression analyses, cell-type-specific ablation, and paracrine activity-deficient vegfc mutant characterization reveal that vEC-autonomous Vegfc and meningeal fibroblast-derived Vegfab and Vegfd are critical for mCP vascularization. These results define molecular cues and cell types essential for directing fenestrated CP vascularization and indicate that vECs' distinct molecular requirements for angiogenesis underlie brain vessel heterogeneity.

中文翻译：

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血管生成的内皮细胞类型特异性分子要求驱动大脑中的有孔血管发育

大脑中的血管内皮细胞 (vECs) 表现出结构和功能的异质性。有孔、可渗透的脑血管介导神经内分泌功能、体液调节和神经免疫反应，但其血管形成仍知之甚少。在这里，我们表明需要血管内皮生长因子 (Vegfs) 的特定组合来选择性地驱动斑马鱼脑脑脉络丛 (mCP) 中的有孔血管形成。我们发现，Vegfab、Vegfc 和 Vegfd 的组合但不是单独的损失会导致 mCP 血管形成严重受损，对邻近的非开孔脑血管形成几乎没有影响，这表明开窗 vEC 特异性血管生成需求。这种 Vegfs 介导的血管选择性模式也涉及 Ccbe1。表达分析，细胞类型特异性消融和旁分泌活性缺陷的 vegfc 突变体表征表明，vEC 自主 Vegfc 和脑膜成纤维细胞衍生的 Vegfab 和 Vegfd 对 mCP 血管形成至关重要。这些结果定义了指导有孔 CP 血管形成所必需的分子线索和细胞类型，并表明 vECs 对血管生成的不同分子要求是脑血管异质性的基础。