Decreased reendothelialization and increased neointima formation with endostatin overexpression in a mouse model of arterial injury.
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.


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 beta-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.
Hutter
Randolph
R
Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, 1425 Madison Ave, New York, NY 10029, USA.
Sauter
Bernhard V
BV
Reis
Ernane D
ED
Roque
Merce
M
Vorchheimer
David
D
Carrick
Francine E
FE
Fallon
John T
JT
Fuster
Valentin
V
Badimon
Juan J
JJ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001157:Arterial Occlusive Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D043169:Endostatins; D004730:Endothelium, Vascular / Q000473:pathology / Q000502:physiology*; D015870:Gene Expression; D005822:Genetic Vectors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019076:Transgenes; D014945:Wound Healing
D043169:Endostatins; D010446:Peptide Fragments; D003094:Collagen