New connections: Multiple paths control vascular integrity

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Science Signaling  31 Jan 2017:
Vol. 10, Issue 464, eaam8349
DOI: 10.1126/scisignal.aam8349

A pair of studies identifies new targets to prevent pathological vascular permeability.

The interconnected endothelial cells that line blood vessels act as a barrier between blood and tissues. The integrity of the intercellular junctions between endothelial cells determines vascular permeability, which is regulated by multiple signaling pathways, including those activated by the receptor VEGFR-2 and its coreceptor NRP1. Although blood vessel leakiness is necessary, in some contexts, such as to allow leukocyte extravasation to fight infection, excessive leakiness can promote edema or the inappropriate movement of cells, such as the metastasis of cancer cells into the blood. Two papers published in Science Signaling reveal new insights into pathways that regulate vascular permeability and have implications for developing drugs to control this process.

Roth et al. discovered that different ligands that triggered the clustering of NRP1 increased vascular permeability without involving VEGFR-2 activation. Experiments with transgenic mice with a form of NRP1 lacking the cytoplasmic domain showed that this domain was required for NRP1-clustering stimuli to enhance leakage from blood vessels. These results have implications for developing therapeutics that reduce pathological vascular permeability and metastasis of cancer cells because most drugs have targeted the VEGFR-dependent pathway, and now a VEGFR-independent pathway must also be considered.

Excessive blood vessel leakiness also leads to fluid buildup in tissue. In stroke patients, too much fluid can accumulate in the brain and cause irreparable damage. Sewduth et al. found that the E3 ubiquitin ligase PDZRN3 destabilized endothelial intercellular junctions and increased vascular permeability. Genetic ablation of PDZRN3 in adult mice decreased the brain edema that occurred after stroke, an effect mimicked by a pharmacological inhibitor of PKCζ, a kinase that destabilizes endothelial intercellular junctions. These results suggest that inhibiting PDZRN3 or its downstream effector PKCζ may prevent the pathological edema that occurs after stroke.

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