Neuregulin1-decreases interleukin-1-induced RhoA activation, myosin light chain phosphorylation, and endothelial hyperpermeability

Neuregulin-1 ( NRG1) is an endogenous growth factor with multiple functions in the embryonic and postnatal brain. The NRG1 gene is large and complex, transcribing more than twenty transmembrane proteins and generating a large number of isoforms in tissue and cell type-specific patterns. Within the brain, NRG1 functions have been studied most extensively in neurons and glia, as well as in the peripheral vasculature. Recently, NRG1 signaling has been found to be important in the function of brain microvascular endothelial cells, decreasing IL1 beta- induced increases in endothelial permeability. In the current experiments, we have investigated the pathways through which the NRG1- beta isoform acts on IL- 1 beta- induced endothelial permeability. Our data show that NRG1- beta increases barrier function, measured by transendothelial electrical resistance, and decreases IL- 1 beta- induced hyperpermeability, measured by dextran- 40 extravasation through a monolayer of brain microvascular endothelial cells plated on transwells. An investigation of key signaling proteins suggests that the effect of NRG1- beta on endothelial permeability is mediated through RhoA activation and myosin light chain phosphorylation, events which affect filamentous actin morphology. In addition, AG825, an inhibitor of the erbB2- associated tyrosine kinase, reduces the effect of NRG1- beta on IL- 1 beta- induced RhoA activation and myosin light chain phosphorylation. These data add to the evidence that NRG1- beta signaling affects changes in the brain microvasculature in the setting of neuroinflammation. J. Neurochem. ( 2016) 136, 250- 257.