Novel role of the IGF-1 receptor in endothelial function and repair: studies in endothelium-targeted IGF-1 receptor transgenic mice.
We recently demonstrated that reducing IGF-1 receptor (IGF-1R) numbers in the endothelium enhances nitric oxide (NO) bioavailability and endothelial cell insulin sensitivity. In the present report, we aimed to examine the effect of increasing IGF-1R on endothelial cell function and repair. To examine the effect of increasing IGF-1R in the endothelium, we generated mice overexpressing human IGF-1R in the endothelium (human IGF-1R endothelium-overexpressing mice [hIGFREO]) under direction of the Tie2 promoter enhancer. hIGFREO aorta had reduced basal NO bioavailability (percent constriction to N(G)-monomethyl-l-arginine [mean (SEM) wild type 106% (30%); hIGFREO 48% (10%)]; P < 0.05). Endothelial cells from hIGFREO had reduced insulin-stimulated endothelial NO synthase activation (mean [SEM] wild type 170% [25%], hIGFREO 58% [3%]; P = 0.04) and insulin-stimulated NO release (mean [SEM] wild type 4,500 AU [1,000], hIGFREO 1,500 AU [700]; P < 0.05). hIGFREO mice had enhanced endothelium regeneration after denuding arterial injury (mean [SEM] percent recovered area, wild type 57% [2%], hIGFREO 47% [5%]; P < 0.05) and enhanced endothelial cell migration in vitro. The IGF-1R, although reducing NO bioavailability, enhances in situ endothelium regeneration. Manipulating IGF-1R in the endothelium may be a useful strategy to treat disorders of vascular growth and repair.
Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, UK.
Helen
H
Imrie
Hema
H
Viswambharan
Piruthivi
P
Sukumar
Afroze
A
Abbas
Richard M
RM
Cubbon
Nadira
N
Yuldasheva
Matthew
M
Gage
Jessica
J
Smith
Stacey
S
Galloway
Anna
A
Skromna
Sheik Taqweer
ST
Rashid
T Simon
TS
Futers
Shouhong
S
Xuan
V Kate
VK
Gatenby
Peter J
PJ
Grant
Keith M
KM
Channon
David J
DJ
Beech
Stephen B
SB
Wheatcroft
Mark T
MT
Kearney
D000818:Animals; D001011:Aorta / Q000502:physiology; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000502:physiology*; D005260:Female; D006706:Homeostasis; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D017526:Receptor, IGF Type 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects
D001786:Blood Glucose; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D017526:Receptor, IGF Type 1