Decreased Reendothelialization and Increased Neointima Formation With Endostatin Overexpression in a Mouse Model of Arterial Injury

Abstract

Background— Impaired endothelial regeneration contributes to arterial lesion formation. Endostatin is a specific inhibitor of endothelial cell growth and induces endothelial cell apoptosis. We examined the effect of endostatin overexpression on reendothelialization and neointima formation in a mouse model of arterial injury. Methods and Results— Mice underwent femoral arterial denudation and received recombinant adenovirus, expressing either murine endostatin (n=19) or control adenoviral vector (n=12), by jugular vein injection. Endostatin gene transfer resulted in high serum levels of endostatin. Strong adenoviral gene expression of β-galactosidase–expressing control vector was detected in liver tissue and was absent in the injured arterial wall at 1 week. Deposits of endostatin protein were detected along the denuded arterial wall and were not seen in the noninjured contralateral artery at 1 week. Endostatin deposits were also absent in the injured artery of control vector–treated animals. Overexpression of endostatin led to decreased reendothelialization and increased apoptosis of luminal endothelial cells 2 and 4 weeks after arterial injury ( P <0.05). In addition, endostatin overexpression resulted in increased neointima formation ( P <0.05). Endothelial apoptosis and neointima area correlated positively with endostatin serum levels, whereas the degree of reendothelialization correlated negatively with endostatin serum levels ( P <0.05). Furthermore, poor reendothelialization correlated with increased neointima formation ( P <0.05). Conclusions— In summary, decreased reendothelialization and enhanced endothelial apoptosis, in response to endostatin overexpression, were associated with increased neointima formation. These findings demonstrate that high serum levels of endostatin are capable of inhibiting endothelial regeneration and promoting arterial lesion growth in conditions of endothelial injury.