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VEGFR tyrosine kinase inhibitor II (VRI) induced vascular insufficiency in zebrafish as a model for studying vascular toxicity and vascular preservation
Li S.4; Dang Y.Y.4; Oi Lam Che G.4; Kwan Y.W.1; Chan S.W.2; Leung G.P.H.3; Lee S.M.Y.4; Hoi M.P.M.4
2014-11-01
Source PublicationToxicology and Applied Pharmacology
ISSN10960333 0041008X
Volume280Issue:3Pages:408-420
Abstract

In ischemic disorders such as chronic wounds and myocardial ischemia, there is inadequate tissue perfusion due to vascular insufficiency. Besides, it has been observed that prolonged use of anti-angiogenic agents in cancer therapy produces cardiovascular toxicity caused by impaired vessel integrity and regeneration. In the present study, we used VEGFR tyrosine kinase inhibitor II (VRI) to chemically induce vascular insufficiency in zebrafish in vivo and human umbilical vein endothelial cells (HUVEC) in vitro to further study the mechanisms of vascular morphogenesis in these pathological conditions. We also explored the possibility of treating vascular insufficiency by enhancing vascular regeneration and repair with pharmacological intervention. We observed that pretreatment of VRI induced blood vessel loss in developing zebrafish by inhibiting angiogenesis and increasing endothelial cell apoptosis, accompanied by down-regulation of kdr, kdrl and flt-1 genes expression. The VRI-induced blood vessel loss in zebrafish could be restored by post-treatment of calycosin, a cardiovascular protective isoflavone. Similarly, VRI induced cytotoxicity and apoptosis in HUVEC which could be rescued by calycosin post-treatment. Further investigation of the underlying mechanisms showed that the PI3K/AKT/Bad cell survival pathway was a main contributor of the vascular regenerative effect of calycosin. These findings indicated that the cardiovascular toxicity in anti-angiogenic therapy was mainly caused by insufficient endothelial cell survival, suggesting its essential role in vascular integrity, repair and regeneration. In addition, we showed that VRI-induced blood vessel loss in zebrafish represented a simple and effective in vivo model for studying vascular insufficiency and evaluating cancer drug vascular toxicities.

KeywordCardiovascular Protective Agents Cardiovascular Toxicity Vascular Insufficiency Zebrafish Model
DOI10.1016/j.taap.2014.09.005
URLView the original
Indexed BySCI
WOS Research AreaPharmacology & Pharmacy ; Toxicology
WOS SubjectPharmacology & Pharmacy ; Toxicology
WOS IDWOS:000344980400003
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Cited Times [WOS]:17   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Affiliation1.Chinese University of Hong Kong
2.Hong Kong Polytechnic University
3.The University of Hong Kong
4.University of Macau
First Author AffilicationUniversity of Macau
Recommended Citation
GB/T 7714
Li S.,Dang Y.Y.,Oi Lam Che G.,et al. VEGFR tyrosine kinase inhibitor II (VRI) induced vascular insufficiency in zebrafish as a model for studying vascular toxicity and vascular preservation[J]. Toxicology and Applied Pharmacology,2014,280(3):408-420.
APA Li S..,Dang Y.Y..,Oi Lam Che G..,Kwan Y.W..,Chan S.W..,...&Hoi M.P.M..(2014).VEGFR tyrosine kinase inhibitor II (VRI) induced vascular insufficiency in zebrafish as a model for studying vascular toxicity and vascular preservation.Toxicology and Applied Pharmacology,280(3),408-420.
MLA Li S.,et al."VEGFR tyrosine kinase inhibitor II (VRI) induced vascular insufficiency in zebrafish as a model for studying vascular toxicity and vascular preservation".Toxicology and Applied Pharmacology 280.3(2014):408-420.
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