PUBLICATION
Synaptotagmin-Like Protein 2a Regulates Angiogenic Lumen Formation via Weibel-Palade Body Apical Secretion of Angiopoietin-2
- Authors
- Francis, C.R., Claflin, S., Kushner, E.J.
- ID
- ZDB-PUB-210416-1
- Date
- 2021
- Source
- Arteriosclerosis, Thrombosis, and Vascular Biology 41(6): 1972-1986 (Journal)
- Registered Authors
- Keywords
- angiopoietin-2, cell membrane, endothelial cells, secretory pathway, synaptotagmins
- MeSH Terms
-
- Angiopoietin-2/genetics
- Angiopoietin-2/metabolism*
- Animals
- Animals, Genetically Modified
- Cells, Cultured
- Exocytosis*
- Human Umbilical Vein Endothelial Cells/metabolism*
- Humans
- Membrane Proteins/genetics
- Membrane Proteins/metabolism*
- Neovascularization, Physiologic*
- Receptor, TIE-2/metabolism
- Signal Transduction
- Weibel-Palade Bodies/genetics
- Weibel-Palade Bodies/metabolism*
- Zebrafish/genetics
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- rab27 GTP-Binding Proteins/metabolism
- PubMed
- 33853352 Full text @ Arterio., Thromb., and Vas. Bio.
Citation
Francis, C.R., Claflin, S., Kushner, E.J. (2021) Synaptotagmin-Like Protein 2a Regulates Angiogenic Lumen Formation via Weibel-Palade Body Apical Secretion of Angiopoietin-2. Arteriosclerosis, Thrombosis, and Vascular Biology. 41(6):1972-1986.
Abstract
Objective Vascular lumen formation requires the redistribution of intracellular proteins to instruct apicobasal polarity, thereby enforcing maturation of both luminal and basal domains. In the absence of proper apical signaling, lumen formation can be distorted leading to lumen collapse and cessation of blood flow. Slp2a (synaptotagmin-like protein-2a) has been implicated in apical membrane signaling; however, the role of Slp2a in vascular lumen formation has never been assessed. Approach and Results: Our results demonstrate that Slp2a is required for vascular lumen formation. Using a 3-dimensional sprouting assay, sub-cellular imaging, and zebrafish blood vessel development, we establish that Slp2a resides at the apical membrane acting as a tether for Rab27a that decorates Weibel-Palade bodies (WPBs). We show that Slp2a regulates exocytic activity of WPBs, thus regulating release of WPB contents into the luminal space during angiogenesis. Angiopoietin-2 is a Tie-2 receptor ligand that is selectively released from WPB secretory granules. We identify a critical role for angiopoietin-2 in regulating endothelial lumenization and show that in the absence of Slp2a, WPB contents cannot fuse with the apical membrane. This disrupts the release of angiopoietin-2 and blocks Tie-2 signaling necessary for proper lumen formation.
Conclusions Our results demonstrate a novel requirement of Slp2a for vascular lumen formation. Moreover, we show that Slp2a is required for the exocytic release of WPB secretory granule cargo during vascular lumen development, and thus is a core upstream component of the WPB secretory pathway. Furthermore, we provide evidence that WPB-housed angiopoietin-2 is required for vascular lumen formation.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping