Published 2021-03-30

Research: Syndecan-4 protein regulates neovascularisation central for cancer growth and retinal diseases

A malignant tumor receives the oxygen and nutrients it needs by creating new blood vessels in a process called angiogenesis. In many retinal diseases, blood vessels also begin to grow out of control due to a lack of oxygen, leading to loss of vision if left untreated. Hitherto, it has been thought that the heparan sulphate proteoglycans in the cell membrane are involved in the binding and presentation of growth factors that stimulate neovascularization, the most important among these is VEGF-A. A recent study by Tampere University’s researchers is now changing this model and opening new treatment options.

A joint study led by Queen Mary University of London, which involved researchers from Tampere University, Tampere University Hospital Tays and the world’s leading eye hospital, Moorsfield in the UK, shows that the deficiency of heparan sulphate, syndecan-4 protein, inhibits neovascularisation in both cancer and retinal diseases.

In addition, the international research team shows that the syndecan-4 protein regulates the function of VE-cadherin, which controls vascular permeability in angiogenesis.

The study, published in the Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) journal of the American Heart Association, was selected as the journal’s study of the month.

“In the study, we show that syndecan-4 is very selectively related to pathological neovascularization caused by diseases such as cancer and retinal diseases,” says Professor and Chief Surgeon Tero Järvinen from Tampere University and Tays.

“Our research findings now open up new opportunities to develop even more specific therapies to prevent neovascularization, which is a key factor in many diseases,” Järvinen says.

VEGF-A inhibitors are used in the treatment of cancer and they have also revolutionised the treatment of retinal diseases. Unfortunately, patients may develop resistance to them, which is related to the pharmacodynamics of medicines. Current drugs kill new blood vessels, leading to a lack of oxygen in the diseased tissue and the emergence of new, easily leaking blood vessels to make up for the lack of oxygen in the tissue.

“We show that syndecan-4 regulates the activity of the VEGF-A only after its binding to the receptor where after it selectively regulates the permeability of new blood vessels,” says Hannele Uusitalo-Järvinen, Chief Physician at the Tays Eye Centre.

“This finding suggests that it is possible to develop a new generation of medicines that would be even more selective than current medicines. These drugs would not destroy the new blood vessels, but would stabilise the leaking blood vessels,” Uusitalo-Järvinen explains.

“With samples collected from diabetes patients, we were able to show that the mechanism we described is active in retinopathy,” she adds.

Giulia De Rossi, Maria Vähätupa, Enrico Cristante, Samantha Arokiasamy, Sidath E. Liyanage, Ulrike May, Laura Pellinen, Hannele Uusitalo-Järvinen, James W. Bainbridge, Tero A.H. Järvinen, James R. Whiteford:  Pathological Angiogenesis Requires Syndecan-4 for Efficient VEGFA-Induced VE-Cadherin Internalization. Arteriosclerosis, Thrombosis and Vascular Biology 2021;41:1374–1389.