Endothelial cell-type-specific molecular requirements for angiogenesis drive fenestrated vessel development in the brain.
Endothelial cell-type-specific molecular requirements for angiogenesis drive fenestrated vessel development in the brain.
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DOI：
10.7554/elife.64295
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发表时间：
2021-01-18
期刊：
影响因子：
7.7
通讯作者：
Matsuoka RL
中科院分区：
文献类型：
--
作者：
Parab S;Quick RE;Matsuoka RL
脑血管内皮细胞（vECs）表现出结构和功能的异质性。开窗通透的脑血管调节神经内分泌功能、体液调节和神经免疫反应；然而，它的血管形成仍然知之甚少。在这里，我们表明血管内皮生长因子（Vegfs）的特定组合需要选择性地驱动斑马鱼髓脑脉络丛（mCP）的开窗血管形成。我们发现Vegfab、Vegfc和Vegfd的联合（而非单个）缺失会导致mCP血管化严重受损，而对邻近非开窗脑血管的形成影响很小，这表明有开窗的vec特异性血管生成需要。这种vegf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乏的vegfc突变特征表明，vec自主vegfc和脑膜成纤维细胞衍生的Vegfab和Vegfd对mCP血管化至关重要。这些结果定义了指导开窗CP血管形成的关键分子线索和细胞类型，并表明vECs对血管生成的独特分子需求是脑血管异质性的基础。
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 suggest that vEC-autonomous Vegfc and meningeal fibroblast-derived Vegfab and Vegfd are critical for mCP vascularization. These results define molecular cues and cell types critical for directing fenestrated CP vascularization and indicate that vECs’ distinct molecular requirements for angiogenesis underlie brain vessel heterogeneity.