Vascular endothelial growth factor enhances angiotensin II-induced aneurysm formation in apolipoprotein E-deficient mice.
OBJECTIVE
Abdominal aortic aneurysm (AAA) development is associated with increased angiogenesis and overexpression of vascular endothelial growth factor (VEGF). Inhibition of angiogenesis results in attenuation of experimental aneurysms. This study investigated the effects of recombinant human (rh)VEGF on experimental aneurysms.


METHODS
Apolipoprotein E-deficient (apoE(-/-)) mice were assigned to one of four groups: (1) normal saline infusion (sham), (2) angiotensin-II (AngII) infusion, (3) AngII infusion plus 100 microg daily rhVEGF for 14 days (AngII+14dVEGF), or (4) AngII infusion plus 100 microg daily rhVEGF for 21 days (AngII+21dVEGF). Aortic maximum diameter and cross-sectional area were determined by magnetic resonance imaging and microscopy. All mice were sacrificed at day 28.


RESULTS
Aneurysms developed in all mice in the AngII+14dVEGF and AngII+21dVEGF groups by day 21 compared with 40% in the AngII group. Treatment with rhVEGF increased maximum aortic diameter (P < .002) and cross-sectional area of aneurysms (P < .005) at day 21. This effect was maintained at day 28 (P < .0005). Decreasing rhVEGF treatment from 21 to 14 days did not attenuate aneurysm formation. Treatment with rhVEGF upregulated matrix metalloproteinase 2 gene expression within the aortic wall (P < .0009).


CONCLUSIONS
Treatment with rhVEGF intensified the formation of AngII-induced aneurysms. Further studies are needed to investigate if antiangiogenic therapy may be a valid medical therapy against aneurysm expansion or rupture.
Choke
Edward
E
St. George's Vascular Institute, London, United Kingdom.
Cockerill
Gillian W
GW
Dawson
Joseph
J
Howe
Franklyn
F
Wilson
William R W
WR
Loftus
Ian M
IM
Thompson
Matthew M
MM
D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology*; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001835:Body Weight; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D018450:Disease Progression; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D015918:Infusion Pumps, Implantable; D007274:Injections, Intraperitoneal; D018810:Magnetic Resonance Angiography; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000008:administration & dosage; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage
D001057:Apolipoproteins E; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse