Loss of insulin signaling in vascular endothelial cells accelerates atherosclerosis in apolipoprotein E null mice.
To determine whether insulin action on endothelial cells promotes or protects against atherosclerosis, we generated apolipoprotein E null mice in which the insulin receptor gene was intact or conditionally deleted in vascular endothelial cells. Insulin sensitivity, glucose tolerance, plasma lipids, and blood pressure were not different between the two groups, but atherosclerotic lesion size was more than 2-fold higher in mice lacking endothelial insulin signaling. Endothelium-dependent vasodilation was impaired and endothelial cell VCAM-1 expression was increased in these animals. Adhesion of mononuclear cells to endothelium in vivo was increased 4-fold compared with controls but reduced to below control values by a VCAM-1-blocking antibody. These results provide definitive evidence that loss of insulin signaling in endothelium, in the absence of competing systemic risk factors, accelerates atherosclerosis. Therefore, improving insulin sensitivity in the endothelium of patients with insulin resistance or type 2 diabetes may prevent cardiovascular complications.
Rask-Madsen
Christian
C
Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.
Li
Qian
Q
Freund
Bryn
B
Feather
Danielle
D
Abramov
Roman
R
Wu
I-Hsien
IH
Chen
Kai
K
Yamamoto-Hiraoka
Junko
J
Goldenbogen
Jan
J
Sotiropoulos
Konstantinos B
KB
Clermont
Allen
A
Geraldes
Pedro
P
Dall'Osso
Claudia
C
Wagers
Amy J
AJ
Huang
Paul L
PL
Rekhter
Mark
M
Scalia
Rosario
R
Kahn
C Ronald
CR
King
George L
GL
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology*; D002448:Cell Adhesion; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012307:Risk Factors; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014664:Vasodilation
D001057:Apolipoproteins E; D007328:Insulin; D019010:Vascular Cell Adhesion Molecule-1
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