Heparanase 2 emerges as key protector of blood vessel integrity

An international research team led by MDI Biological Laboratory President Hermann Haller, M.D. and postdoctoral researcher Yannic Becker, Ph.D. has discovered that a little-known molecule, heparanase 2 (Hpa2), plays a critical role in maintaining blood vessels' integrity.

Malfunctions in the vasculature are increasingly seen as an underlying driver of a wide array of diseases.

The findings were published in the peer-reviewed journal, Arteriosclerosis, Thrombosis, and Vascular Biology. They suggest that Hpa2, which occurs naturally in vertebrates and other animals, could be useful in new therapies for vision and chronic kidney diseases, cardiovascular disease and cancer.

The vasculature's interior is lined by the endothelium, a single layer of cells that control what passes in and out of the blood stream. Its permeability and structure depend on heparan sulfate proteoglycans - sugar-based molecules that anchor signaling proteins such as vascular endothelial growth factor (VEGF) to the cells.

The researchers found that Hpa2, until now poorly understood, also binds strongly to heparan sulfate at the same anchor site, and can block growth-factor signaling.

VEGF is essential for normal tissue growth and repair. But when overactive it can cause leaky blood vessels, contributing to diseases such as diabetic retinopathy and macular degeneration in the eye, and protein loss in the kidney (proteinuria). It can also aid cancer cells' ability to highjack the vasculature for their own sustenance.

Working with zebrafish, mouse kidneys and human endothelial cell cultures, the research team showed that when Hpa2 is absent, vessels lose their structural integrity and become abnormally leaky. Introducing manufactured Hpa2 reversed that fragility, restoring normal vascular function.

Usually most of our blood vessels are pretty tight, but we saw that if we take out heparanase 2, we have an increased flux of molecules and water into the interstitium. This discovery identifies Hpa2 as an essential safeguard for the blood vessel wall."

Yannic Becker, Ph.D., study's first author

Key findings

• Hpa2 is conserved across vertebrates and circulates in the bloodstream.
• Hpa2 competes with VEGF and other growth factors for binding to endothelial cells, dampening overactive growth-factor signaling.
• Loss of Hpa2 increases vascular permeability and disrupts endothelial structure in zebrafish.
• Application of recombinant Hpa2 blocks VEGF-induced permeability and restores vascular function in mouse kidneys.

"Hpa2 shows promising pharmaceutical potential," said Haller, the article's senior author. "Current therapies for vascular disease often focus on blocking growth factor signaling, but Hpa2 may offer a more natural mechanism to restore balance without adverse side effects."

Funding

This research was supported by the German Research Foundation (DFG), the Scott MacKenzie Foundation and the U.S. National Institutes of Health Institutional Development Award (IDeA) program (P20GM103423 and P20GM104318).