Heparanase 2 Modulates Vascular Permeability via Heparan Sulfate-Dependent Growth Factor Signaling

Area of Science:

• Vascular Biology
• Endothelial Cell Biology
• Proteoglycan Function

Background:

• Vessel-lining endothelial cells (ECs) utilize heparan sulfate (HS) proteoglycans for vascular homeostasis.
• Heparanase 2 (Hpa2) is a nonenzymatic protein that binds HS and has poorly understood functions.
• This study investigates the role of endogenous Hpa2 in the vertebrate vascular system.

Purpose of the Study:

• To characterize the functions of endogenous Hpa2 in the vertebrate vascular system.
• To elucidate the molecular mechanisms by which Hpa2 influences vascular integrity.
• To explore the potential therapeutic applications of Hpa2.

Main Methods:

• Utilized zebrafish larvae as a model organism, employing CRISPR-Cas9 and morpholino antisense strategies for Hpa2 loss-of-function (LOF).
• Assessed vascular permeability, blood vessel architecture, and EC morphology using transgenic zebrafish and transmission electron microscopy.
• Generated recombinant Hpa2 (rHpa2) for functional studies in endothelial tissues, zebrafish, and mice.

Main Results:

• Hpa2 is expressed in hepatic tissue and localized to the vasculature in zebrafish and mammals.
• Hpa2 LOF increased vascular permeability, altered EC and extracellular matrix morphology, and reduced HS levels.
• rHpa2 rescued Hpa2 LOF phenotypes, competed with FGF2 and VEGFA165 for EC surface binding, and inhibited VEGFA165-induced permeability.

Conclusions:

• Hpa2 functions as a circulating molecule crucial for maintaining vascular integrity.
• Hpa2 regulates vascular HS-dependent growth factor signaling, impacting vascular homeostasis.
• The findings suggest Hpa2-related vascular function and potential therapeutic utility.