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Assessing Therapeutic Angiogenesis in a Murine Model of Hindlimb Ischemia
Published on: June 8, 2019
Opposite effects of WEB2086 on angiogenesis in atheromas and ischemic hindlimb of apoE gene deficient mice
Shuang Wang1, Ya-ling Tang, Yong-zong Yang
1Department of Pathophysiology, Xiangya Medical College, Central South University, Changsha 410078, China.
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.
Conclusion:
The study provides evidence that WEB2086 can inhibit angiogenesis in atherosclerotic plaque but promote it in ischemic hindlimb.
Insights
Platelet activating factor receptor antagonist WEB2086 inhibits plaque angiogenesis but promotes blood flow and capillary density in ischemic hindlimbs of mice. This dual effect highlights its potential in treating atherosclerosis and ischemia.
Area of Science:
- Cardiovascular Research
- Angiogenesis Studies
- Pharmacological Intervention
Background:
- Platelet activating factor receptor (PAFR) is implicated in atherosclerosis.
- Previous research suggests a link between PAFR and the development of atherosclerotic lesions.
Purpose of the Study:
- To investigate the effect of WEB2086, a PAFR antagonist, on angiogenesis.
- To evaluate WEB2086's impact on atherosclerotic plaque and ischemic hindlimb in apolipoprotein E-deficient mice.
Main Methods:
- Apolipoprotein E-deficient mice were fed a cholesterol-rich diet to induce atherosclerosis.
- Hindlimb ischemia was surgically induced, and mice received WEB2086 in drinking water.
- Angiogenesis was assessed using CD31 staining, plaque sprouting, laser Doppler perfusion imaging, and von Willebrand factor expression.
Main Results:
- WEB2086 significantly reduced lesion-to-aorta levels and intimal capillary density in atherosclerotic plaques.
- Administration of WEB2086 decreased plaque-associated sprouting in the aorta.
- WEB2086 markedly increased blood flow and capillary density in the ischemic hindlimb.
Conclusions:
- WEB2086 demonstrates a dual role in angiogenesis: inhibiting it in atherosclerotic plaques.
- Conversely, WEB2086 promotes angiogenesis in ischemic hindlimb tissues.
- These findings suggest WEB2086's potential therapeutic applications in cardiovascular diseases.
