Key result
Hpa2 loss increases vascular permeability, which is reversed by recombinant Hpa2 via growth factor signaling.
Hpa2 is identified as a circulating molecule that maintains vascular integrity by regulating heparan sulfate-dependent growth factor signaling, highlighting a novel mechanism for vascular homeostasis.
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 VEGFA 165 (vascular endothelial growth factor A 165 ) for binding on the EC surface and consequently reduced the signal response these factors elicit. rHpa2 prevented VEGFA 165 -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.
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Becker et al. (2025) studied Vascular permeability and homeostasis. Hpa2 loss-of-function and recombinant Hpa2 was evaluated on Vascular permeability, blood vessel architecture, and endothelial cell morphology. Hpa2 loss-of-function increased vascular permeability in zebrafish, a phenotype rescued by recombinant Hpa2 via modulation of heparan sulfate-dependent growth factor signaling.
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