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PreprintCC BY-NC-NDbioRxiv

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

  • L. D. Buck
  • V. Thakur
  • A. G. Storm
  • F. Z. Bozdag
  • N. J. Lee
  • J. X. Leong
  • E. N. Kazazic
  • A. E. Lam
  • A. A. Getz
  • R. L. Matsuoka1
  1. 1Cleveland Clinic Research
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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.

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Cite

BibTeXRIS
BibTeX
@misc{buck2026lymphangiogenic,
  title = {{The lymphangiogenic Ccbe1-Adamts-Vegfc axis shapes cerebrovascular regionalization via selective patterning of fenestrated vascular beds}},
  author = {L. D. Buck and V. Thakur and A. G. Storm and F. Z. Bozdag and N. J. Lee and J. X. Leong and E. N. Kazazic and A. E. Lam and A. A. Getz and R. L. Matsuoka},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.14.759138},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.14.759138v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - The lymphangiogenic Ccbe1-Adamts-Vegfc axis shapes cerebrovascular regionalization via selective patterning of fenestrated vascular beds
AU  - L. D. Buck
AU  - V. Thakur
AU  - A. G. Storm
AU  - F. Z. Bozdag
AU  - N. J. Lee
AU  - J. X. Leong
AU  - E. N. Kazazic
AU  - A. E. Lam
AU  - A. A. Getz
AU  - R. L. Matsuoka
PY  - 2026
DA  - 2026/10/14
PB  - bioRxiv
DO  - 10.64898/2026.10.14.759138
UR  - https://www.biorxiv.org/content/10.64898/2026.10.14.759138v1
AB  - 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.
ER  -