VEGF and Vascular Permeability
Lena Claesson-Welsh, Ph.D.
University of Uppsala
In the normal vasculature, arterial vessels release fluid and small molecules across the vessel wall. Leakage of larger molecules and extravasation of inflammatory cells, however, require that gaps be formed at endothelial cell–cell contacts. These contacts are composed of tight and adherens junctions. The formation of gaps at adherens junctions is induced by growth factors such as vascular endothelial growth factor (VEGF) and inflammatory cytokines such as histamine and bradykinin. It is well established that there is elevated vascular leakage in several diseases, particularly when accompanied by inflammation. Such diseases include cancer and eye diseases, where leakage may be chronic. In diseases such as stroke and myocardial infarction, leakage may be debilitating in the acute phase. Excess leakage leads to edema, tissue damage, and disease progression, and it prevents efficient drug penetration into the edematous tissue. Therefore, drugs that specifically suppress leakage would meet a clinical need.
To find new drug targets for leakage prevention, Lena Claesson-Welsh and her coworkers have delineated the signaling pathway induced by VEGF. Src family kinases (SFKs) are key molecules in this pathway. SFKs are cytoplasmic, structurally related tyrosine kinases. The SFKs Src, Yes, and Fyn are expressed in endothelial cells. Although Src has received most attention in the field thus far, we show that Yes is the most abundant SFK in endothelial cells, and it is located at endothelial adherens junctions. In response to VEGF, Yes phosphorylates the adherens junction molecule vascular endothelial (VE)-cadherin. These phosphorylation reactions have been correlated with opening of endothelial gaps and leakage. Unexpectedly, our data show that VE-cadherin must be phosphorylated on tyrosine in order for junctions to organize correctly and be stable. Thus, mice with genetic inactivation of Yes in endothelial cells respond to VEGF with more enhanced leakage. Transmission electron microscopy analyses show that in the absence of Yes, the adherens junctions appear less dense and weaker. Therefore, inhibitors of Src kinase activity, which also inhibit the activities of Yes and Fyn, will destabilize junctions and potentially increase rather than suppress leakage. We are now seeking other strategies to inhibit VEGF-induced vascular leakage.