Endothelial cell-type-specific molecular requirements for angiogenesis drive fenestrated vessel development in the brain

• Published in: eLife 2021-01, Vol.10
• Main Authors: Parab, Sweta, Quick, Rachael E, Matsuoka, Ryota L
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Brain; Brain - growth & development; Brain - metabolism; central nervous system; Choroid plexus; Developmental Biology; Endothelial cells; Endothelial Cells - metabolism; Endothelial growth factors; Endothelium; genetic interactions; Genotype & phenotype; Growth factors; Immune response; Mammals; Medulla oblongata; Neovascularization, Physiologic - genetics; Neuroendocrine system; Paracrine signalling; Pattern formation; Signal Transduction; Structure-function relationships; Transmission electron microscopy; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor C - genetics; Vascular Endothelial Growth Factor C - metabolism; Vascular Endothelial Growth Factor D - genetics; Vascular Endothelial Growth Factor D - metabolism; Vascularization; Vegfs; Veins & arteries; Zebrafish; Zebrafish - genetics; Zebrafish - physiology; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.64295

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 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.