Metalloproteinase-dependent Cleavage of Neuregulin and Autocrine Stimulation of Vascular Endothelial Cells

Inflammation is often accompanied by robust angiogenesis. Vascular endothelial cells (ECs) express erbB receptors and their ligand, neuregulin-1, and can respond to neuregulin by proliferation and angiogenesis. We hypothesized that some growth factor-like responses of ECs to inflammatory cytokines can be explained by cleavage of transmembrane neuregulin with subsequent release of its extracellular epidermal growth factor-like-containing domain and autocrine activation. Using a model of cultured human ECs, we found that interleukin-6 or interferon-gamma causes rapid cleavage and release of transmembrane neuregulin. Inhibitors of metalloproteinases abolish this effect. The addition of an inhibitor of tumor necrosis factor-alpha converting enzyme (TACE) blocks cytokine-induced neuregulin release. Silencing of TACE expression increases the amount of basal proneuregulin present in ECs but does not block neuregulin release in response to phorbol myristate acetate (PMA), suggesting that other proteinases are responsible for mediating protein kinase C-dependent cleavage. Cytokines capable of inducing neuregulin cleavage stimulated ERK activation and in vitro angiogenesis (Matrigel cord formation). This effect is blocked by inhibitors that block neuregulin cleavage, erbB protein tyrosine kinase inhibitors, or antineuregulin-neutralizing antibodies. Cytokine-activated metalloproteinase cleavage of neuregulin may play an important role in autocrine activation of EC signaling pathways, contributing to key biological effects, perhaps including inflammation-associated angiogenesis.