TY - JOUR TI - Local angiogenic interplay of Vegfc/d and Vegfa controls brain region-specific emergence of fenestrated capillaries AU - Parab, Sweta AU - Card, Olivia A AU - Chen, Qiyu AU - America, Michelle AU - Buck, Luke D AU - Quick, Rachael E AU - Horrigan, William F AU - Levkowitz, Gil AU - Vanhollebeke, Benoit AU - Matsuoka, Ryota L A2 - Gleeson, Joseph G A2 - Bronner, Marianne E A2 - Taylor, Michael R VL - 12 PY - 2023 DA - 2023/05/16 SP - e86066 C1 - eLife 2023;12:e86066 DO - 10.7554/eLife.86066 UR - https://doi.org/10.7554/eLife.86066 AB - Fenestrated and blood-brain barrier (BBB)-forming endothelial cells constitute major brain capillaries, and this vascular heterogeneity is crucial for region-specific neural function and brain homeostasis. How these capillary types emerge in a brain region-specific manner and subsequently establish intra-brain vascular heterogeneity remains unclear. Here, we performed a comparative analysis of vascularization across the zebrafish choroid plexuses (CPs), circumventricular organs (CVOs), and retinal choroid, and show common angiogenic mechanisms critical for fenestrated brain capillary formation. We found that zebrafish deficient for Gpr124, Reck, or Wnt7aa exhibit severely impaired BBB angiogenesis without any apparent defect in fenestrated capillary formation in the CPs, CVOs, and retinal choroid. Conversely, genetic loss of various Vegf combinations caused significant disruptions in Wnt7/Gpr124/Reck signaling-independent vascularization of these organs. The phenotypic variation and specificity revealed heterogeneous endothelial requirements for Vegfs-dependent angiogenesis during CP and CVO vascularization, identifying unexpected interplay of Vegfc/d and Vegfa in this process. Mechanistically, expression analysis and paracrine activity-deficient vegfc mutant characterization suggest that endothelial cells and non-neuronal specialized cell types present in the CPs and CVOs are major sources of Vegfs responsible for regionally restricted angiogenic interplay. Thus, brain region-specific presentations and interplay of Vegfc/d and Vegfa control emergence of fenestrated capillaries, providing insight into the mechanisms driving intra-brain vascular heterogeneity and fenestrated vessel formation in other organs. KW - brain angiogenesis KW - central nervous system KW - vascular heterogeneity KW - fenestrated endothelial cells KW - Vegfs KW - Wnts JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -