Endostatin limits pulmonary endothelial repair via RhoA inactivation

Abstract

Endothelial repair following vascular injury involves cell proliferation and migration. Endostatin regulates cell proliferation, and is essential for maintenance of a functional vascular barrier. However, elevated endostatin levels correlate with severity of inflammatory lung damage. The source of endostatin or its role in progression of vascular disease is not known. We reasoned endostatin release by lung endothelium during an injury event contributes to pulmonary vascular damage by limiting endothelial proliferation and migration; thus slowing barrier restoration. LPS increased endostatin expression in lung tissue in vivo and in pulmonary microvascular endothelial cells (PMVECs) in vitro. LPS caused translocation of endostatin from peri‐nuclear regions to cell membranes in PMVECs consistent with release of endogenously synthesized endostatin. LPS inhibits PMVEC proliferation and wound healing, an effect exacerbated by exogenous application of endostatin. Endostatin decreased RhoA activity in PMVECs implicating the RhoA pathway in endostatin signaling.Conclusioninflammation induces endostatin release from endothelium sufficient to limit lung vascular repair. Supported by HL102296 and HL 110803.