The lymphangiogenic Ccbe1-Adamts-Vegfc axis shapes cerebrovascular regionalization via selective patterning of fenestrated vascular beds

Abstract

Organ development and function require regional specialization of vascular networks, yet the underlying molecular mechanisms remain poorly understood. Here, we identify a non-canonical role for the lymphangiogenic Ccbe1-Adamts-Vegfc axis in shaping cerebrovascular regionalization in zebrafish. A ccbe1 knock-in reporter revealed highly restricted expression in the developing brain, with its genetic loss causing early vascularization defects at the pineal gland-choroid plexus interface. Simultaneous Vegfa signaling deficiency markedly exacerbated these regional vascular defects, accompanied by disrupted blood flow, local hemorrhage, and choroid plexus epithelial disorganization, while largely preserving neighboring barrier-forming vessels. Loss of vegfc closely phenocopied ccbe1 mutant defects, with fenestrated vascular patterning requiring both Vegfr2 and Vegfr3 signaling, whereas disruption of adamts3 and adamts14 indicated region-specific requirements for Vegfc-activating proteases. Conversely, pineal gland-specific overexpression of activated Vegfc partially rescued the vascularization defects. Collectively, these findings suggest that spatially restricted Ccbe1-Adamts-Vegfc activity provides angiogenic signaling specificity enabling fenestrated cerebrovascular patterning and regionalization.