PUBLICATION
Heparanase 2 Modulates Vascular Permeability via Heparan Sulfate-Dependent Growth Factor Signaling
- Authors
- Becker, Y., Tkachuk, S., Jörns, A., Shushakova, N., Rong, S., Alwakaa, A., Hegermann, J., Schenk, H., Kiyan, Y., Haller, H.
- ID
- ZDB-PUB-250821-8
- Date
- 2025
- Source
- Arteriosclerosis, Thrombosis, and Vascular Biology : (Journal)
- Registered Authors
- Keywords
- endothelial cells, heparan sulfate proteoglycans, heparanase, homeostasis, zebrafish
- Datasets
- GEO:GSE276120
- MeSH Terms
-
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Animals, Genetically Modified
- Capillary Permeability*
- Mice
- Humans
- Heparitin Sulfate*/metabolism
- Vascular Endothelial Growth Factor A*/metabolism
- Liver/blood supply
- Glucuronidase*/genetics
- Glucuronidase*/metabolism
- Endothelial Cells*/enzymology
- Endothelial Cells*/ultrastructure
- Cells, Cultured
- Animals
- Signal Transduction
- PubMed
- 40836917 Full text @ Arterio., Thromb., and Vas. Bio.
Citation
Becker, Y., Tkachuk, S., Jörns, A., Shushakova, N., Rong, S., Alwakaa, A., Hegermann, J., Schenk, H., Kiyan, Y., Haller, H. (2025) Heparanase 2 Modulates Vascular Permeability via Heparan Sulfate-Dependent Growth Factor Signaling. Arteriosclerosis, Thrombosis, and Vascular Biology. :.
Abstract
Background Vessel-lining endothelial cells (ECs) rely on heparan sulfate (HS) proteoglycans to regulate vascular permeability and to maintain vascular homeostasis. Hpa2 (heparanase 2) is a little-known, nonenzymatic, HS-binding protein. We hypothesized major functions and thus characterized the role of endogenous Hpa2 in the vertebrate vascular system.
Methods We use zebrafish larvae as our primary animal model. Hpa2 loss-of-function (LOF) was induced by CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) and morpholino antisense strategies. We assessed vascular permeability, blood vessel architecture, and EC morphology using transgenic zebrafish and transmission electron microscopy. rHpa2 (recombinant heparanase 2) was generated to study the functionality of Hpa2 in endothelial tissue cultures, zebrafish, and mice.
Results We detected Hpa2 expression in hepatic tissue and localized Hpa2 protein in the vasculature of zebrafish and mammals. Hpa2 LOF increased zebrafish vascular permeability and altered EC and extracellular matrix morphology. rHpa2 rescued the Hpa2 LOF phenotype. Hpa2 LOF reduced HS levels and caused EC gene expression changes involved in signal transduction. rHpa2 competed with growth factors FGF2 (fibroblast growth factor-2) and VEGFA165 (vascular endothelial growth factor A165) for binding on the EC surface and consequently reduced the signal response these factors elicit. rHpa2 prevented VEGFA165-induced vascular permeability in murine ex vivo kidneys. Pharmacological inhibition of FGF2/VEGFR (VEGF receptor) signaling alleviated the Hpa2 LOF phenotype in zebrafish.
Conclusions We suggest that Hpa2 is a circulating molecule that maintains vascular integrity by regulating vascular HS-dependent growth factor signaling. Our model outlines Hpa2-related vascular function and could indicate therapeutic utilities.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping