Neuregulin activation of ErbB receptors in vascular endothelium leads to angiogenesis

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Abstract
The ErbB, or epidermal growth factor receptor (EGF-r), family of transmembrane tyrosine kinase receptors has been demonstrated to play an important role in growth regulation and intracellular signaling in a wide variety of cell types. Targeted deletion of neuregulin (an ErbB ligand) in mice results in endocardial cushion abnormalities, suggesting that these receptor-ligand interactions have important effects on vascular endothelial growth and development. To study the role of ErbB receptor signaling in vascular endothelium, we investigated the expression pattern of the various receptor family members and the effect of ErbB receptor stimulation in human umbilical vein endothelial cells (HUVEC). We demonstrate that ErbB2 (neu), ErbB3, and ErbB4 are highly expressed, whereas ErbB1 (EGF-r) is undetectable. Stimulation of HUVEC with recombinant neuregulin-β (an ErbB3/4 ligand) induces rapid calcium fluxes, receptor tyrosine phosphorylation, and cell proliferation. We demonstrate marked in vitro and in vivo angiogenic responses to neuregulin-β, which are independent of vascular endothelial cell growth factor. These findings support an important role for the ErbB family of receptors in endothelial cell signaling and function, including neuregulin-induced angiogenesis.