Defining a novel molecular mechanism in VEGF-induced vascular hyperpermeability

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Blood vessel disease can cause blindness, lung dysfunction, stroke and heart attacks, either because poor blood flow starves tissues of oxygen and nutrients or because blood vessels in oxygen-starved tissues are often leaky and thereby cause tissue swelling and promote inflammation. The therapeutic stimulation of new vessel growth with the growth factor VEGF is a promising treatment for these conditions. However, a side effect of stimulating blood vessel growth with VEGF in adults is increased blood vessel leak that impairs organ function, especially if it occurs in the heart, brain, eye and lung. To understand the mechanism through which VEGF causes either blood vessel growth or blood vessel leak, we have altered its ability to signal through a molecule termed NRP1, which conveys signals from VEGF into the endothelial cells that form the inner lining of blood vessels. Our pilot experiments suggest that NRP1 can be targeted in a specific way to block blood vessel leak without affecting blood vessel growth. To identify the mechanism through which NRP1 causes blood vessel leak, we will alter its function in experimental models that affect eye, skin or lung vessel function and use tissue culture models of endothelial cells to define NRP1's interactions with other signalling molecules that play key roles in vascular leak. Our findings will provide key information on how vessel leak might be stemmed in acute and chronic diseases with dysfunctional blood vessels. This research will not have an immediate clinical impact, but may help other researchers to design better therapies that can stem vessel leak and allow the stimulation of new vessel growth without increasing tissue swelling.