PUBLICATION
Oscillatory contractile forces refine endothelial cell-cell interactions for continuous lumen formation governed by Heg1/Ccm1
- Authors
- Yin, J., Maggi, L., Wiesner, C., Affolter, M., Belting, H.G.
- ID
- ZDB-PUB-240910-4
- Date
- 2024
- Source
- Angiogenesis 27(4): 845-860 (Journal)
- Registered Authors
- Affolter, Markus, Belting, Heinz-Georg Paul (Henry)
- Keywords
- Actomyosin contractility, Anastomosis, Cerebral cavernous malformations (CCMs), Endothelial cells, Heg1, Krit1, Lumen, Oscillation
- MeSH Terms
-
- Actomyosin/metabolism
- Animals
- Cell Communication*
- Endothelial Cells*/metabolism
- Intercellular Junctions/metabolism
- KRIT1 Protein*/genetics
- KRIT1 Protein*/metabolism
- Neovascularization, Physiologic
- Zebrafish*/embryology
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- PubMed
- 39249713 Full text @ Angiogenesis
Citation
Yin, J., Maggi, L., Wiesner, C., Affolter, M., Belting, H.G. (2024) Oscillatory contractile forces refine endothelial cell-cell interactions for continuous lumen formation governed by Heg1/Ccm1. Angiogenesis. 27(4):845-860.
Abstract
The formation and organization of complex blood vessel networks rely on various biophysical forces, yet the mechanisms governing endothelial cell-cell interactions under different mechanical inputs are not well understood. Using the dorsal longitudinal anastomotic vessel (DLAV) in zebrafish as a model, we studied the roles of multiple biophysical inputs and cerebral cavernous malformation (CCM)-related genes in angiogenesis. Our research identifies heg1 and krit1 (ccm1) as crucial for the formation of endothelial cell-cell interfaces during anastomosis. In mutants of these genes, cell-cell interfaces are entangled with fragmented apical domains. A Heg1 live reporter demonstrated that Heg1 is dynamically involved in the oscillatory constrictions along cell-cell junctions, whilst a Myosin live reporter indicated that heg1 and krit1 mutants lack actomyosin contractility along these junctions. In wild-type embryos, the oscillatory contractile forces at junctions refine endothelial cell-cell interactions by straightening junctions and eliminating excessive cell-cell interfaces. Conversely, in the absence of junctional contractility, the cell-cell interfaces become entangled and prone to collapse in both mutants, preventing the formation of a continuous luminal space. By restoring junctional contractility via optogenetic activation of RhoA, contorted junctions are straightened and disentangled. Additionally, haemodynamic forces complement actomyosin contractile forces in resolving entangled cell-cell interfaces in both wild-type and mutant embryos. Overall, our study reveals that oscillatory contractile forces governed by Heg1 and Krit1 are essential for maintaining proper endothelial cell-cell interfaces and thus for the formation of a continuous luminal space, which is essential to generate a functional vasculature.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping