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Updated: Jul 13, 2026
In Vitro Model of Coronary Angiogenesis
Published on: March 10, 2020
In vivo angiogenesis is suppressed by unsaturated vitamin E, tocotrienol
Kiyotaka Nakagawa1, Akira Shibata, Shinji Yamashita
1Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science, Tohoku University, Sendai 981-8555, Japan.
Abstract:
Antiangiogenic therapy using drugs and food components is a recognized strategy for the prevention of various angiogenesis-mediated disorders such as tumor growth, diabetic retinopathy, and rheumatoid arthritis. Our preliminary cell culture studies, using both bovine aortic endothelial cells and human umbilical vein endothelial cells (HUVEC) on screening for food-derived antiangiogenic compounds, showed tocotrienol (T3), an unsaturated version of vitamin E, to be a potential angiogenic inhibitor. We therefore investigaged the in vivo antiangiogenic properties of T3 using 2 well-characterized angiogenic models [mouse dorsal air sac (DAS) assay and the chick embryo chorioallantoic membrane (CAM) assay]. In the DAS assay, the increased neovascularization (angiogenesis index, 4.8 +/- 0.6) in tumor cell-implanted mice was suppressed (angiogenesis index, 2.7 +/- 0.6) by dietary supplementation of 10 mg T3-rich oil/d (equivalent to 4.4 mg T3/d). In the CAM assay, T3 (500-1000 microg/egg) inhibited new blood vessel formation on the growing CAM and increased the frequency of avascular zone (36-50%). To evaluate the antiangiogenic mechanism, we conducted cell-culture studies and found that T3 significantly reduced fibroblast growth factor -induced proliferation, migration, and tube formation in HUVEC (P < 0.05), with delta-T3 having the highest activity. Western blot analysis revealed that delta-T3 suppressed the phosphorylation of phosophoinositide-dependent protein kinase (PDK) and Akt, and increased the phosphorylation of apoptosis signal-regulating kinase and p38 in fibroblast growth factor-treated HUVEC, indicating that the antiangiogenic effects of T3 are associated with changes in growth factor-dependent phosphatidylinositol-3 kinase /PDK/Akt signaling as well as induction of apoptosis in endothelial cells. Our findings suggest that T3 has potential as a therapeutic dietary supplement for preventing angiogenic disorders, and therefore future clinical study will be required to evaluate the efficacy and safety of T3.
Insights
Tocotrienol (T3), a form of vitamin E, shows promise in preventing diseases driven by new blood vessel growth. In animal studies, T3 significantly reduced blood vessel formation, suggesting its potential as a dietary supplement.
Area of Science:
- Biochemistry and Molecular Biology
- Nutritional Science
- Vascular Biology
Background:
- Antiangiogenic therapy is crucial for managing disorders like cancer and diabetic retinopathy.
- Food-derived compounds are being explored as natural antiangiogenic agents.
- Tocotrienol (T3), an unsaturated vitamin E form, was identified in preliminary studies as a potential inhibitor of angiogenesis.
Purpose of the Study:
- To investigate the in vivo antiangiogenic properties of tocotrienol (T3).
- To elucidate the cellular mechanisms underlying T3's antiangiogenic effects.
Main Methods:
- In vivo assessment using mouse dorsal air sac (DAS) and chick embryo chorioallantoic membrane (CAM) assays.
- In vitro studies using human umbilical vein endothelial cells (HUVEC) to evaluate proliferation, migration, and tube formation.
- Western blot analysis to examine signaling pathways, including PDK/Akt and apoptosis-related kinases.
Main Results:
- Dietary T3 supplementation significantly suppressed neovascularization in the DAS assay.
- T3 inhibited new blood vessel formation and increased avascular zones in the CAM assay.
- T3 reduced fibroblast growth factor-induced HUVEC proliferation, migration, and tube formation, with delta-T3 showing the highest activity.
- Western blot analysis indicated T3 suppresses the PI3K/PDK/Akt pathway and promotes apoptosis in endothelial cells.
Conclusions:
- Tocotrienol (T3) exhibits significant in vivo and in vitro antiangiogenic properties.
- The antiangiogenic mechanism involves modulation of the PI3K/PDK/Akt pathway and induction of endothelial cell apoptosis.
- T3 demonstrates potential as a therapeutic dietary supplement for preventing angiogenesis-related disorders, warranting further clinical investigation.
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