Opposite effects of WEB2086 on angiogenesis in atheromas and ischemic hindlimb of apoE gene deficient mice.
BACKGROUND
Our previous research has suggested that platelet activating factor receptor was related to atherosclerosis. The present study investigated the effect of a platelet activating factor receptor antagonist-WEB2086 on angiogenesis in aortal plaque and ischemic hindlimb of apolipoprotein E-deficient mice.


METHODS
Eight-week-old apolipoprotein E-deficient mice were fed with a 0.15% cholesterol diet to develop advanced lesions. At age 32 weeks unilateral hindlimb ischemia was surgically induced and the mice were divided into two groups: with or without WEB2086 mixed with their drinking water (4.3 mg in 100 ml). At age 40 weeks blood was collected from the orbit for measurement of serum lipids and an enzyme linked immunosorbent assay was used to determine platelet activating factor and oxidized low density lipoprotein in the gastrocnemius and aorta. Whole-Mount CD31 stain and plaque-associated sprouting have been used to estimate angiogenesis in plaque from the aorta and laser Doppler perfusion imaging and immunohistochemical expression of von Willebrand factor have been used to estimate angiogenesis in ischemic hindlimb.


RESULTS
The lipid composition of serum was not different between the groups. However, the amount of platelet activating factor and oxidized low density lipoprotein detected in the aorta was significantly higher than that in the gastrocnemius of ischemic hindlimb. The ratio of lesion to aorta levels was significantly reduced by administration of WEB2086, (31.52 +/- 6.18)% vs (55.58 +/- 8.34)%, P < 0.01. The mean density of intimal capillaries in atherosclerotic plaque, (31.13 +/- 9.20)% vs (57.74 +/- 11.28)%, P < 0.01, and the mean number of sprouts per aorta were significantly reduced, 183.92 +/- 34.17 vs 392.54 +/- 76.79, P < 0.01, in the WEB2086 group. Blood flow (0.85 +/- 0.12 vs 0.45 +/- 0.06, P < 0.01) and capillary density of ischemic hindlimb (1.18 +/- 0.17 vs 0.53 +/- 0.09, P < 0.01) were markedly increased in apolipoprotein E-deficient mice treated with WEB2086 versus controls.


CONCLUSIONS
The study provides evidence that WEB2086 can inhibit angiogenesis in atherosclerotic plaque but promote it in ischemic hindlimb.
Wang
Shuang
S
Department of Pathophysiology, Xiangya Medical College, Central South University, Changsha 410078, China.
Tang
Ya-ling
YL
Yang
Yong-zong
YZ
Xu
Zeng-xiang
ZX
Peng
Kuang
K
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000503:physiopathology*; D001381:Azepines / Q000494:pharmacology*; D002196:Capillaries; D002784:Cholesterol / Q000097:blood; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000503:physiopathology*; D008077:Lipoproteins, LDL / Q000097:blood / Q000502:physiology; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010972:Platelet Activating Factor / Q000032:analysis; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000494:pharmacology*
D001057:Apolipoproteins E; D001381:Azepines; D008077:Lipoproteins, LDL; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; C099252:oxidized low density lipoprotein; C039351:platelet activating factor receptor; C052518:WEB 2086; D002784:Cholesterol