title: Crocetin, a carotenoid derivative, inhibits VEGF-induced angiogenesis via suppression of p38 phosphorylation.
abstract: We evaluated the protective effects of crocetin against angiogenesis induced by vascular endothelial growth factor (VEGF). Crocetin, the aglycone of crocin carotenoids, is found in saffron crocus (Crocus sativus L.) and gardenia fruit (Gardenia jasminoides Ellis). The effects of crocetin on VEGF-induced angiogenesis were examined by in vitro tube formation assays and following 14-day co-culture of human umbilical vein endothelial cells (HUVECs) and fibroblasts. The anti-angiogenic mechanism of crocetin was evaluated by examining its effects on VEGF-induced proliferation and migration of human retinal microvascular endothelial cells (HRMECs) and phosphorylation of p38. Vascular endothelial (VE)-cadherin, zonula occludens (ZO-1) and occludin, which are adherens and tight junction proteins, respectively, play a major role in the control of vascular permeability. Therefore, we tested effects of crocetin on adhesion molecule dissociation induced by VEGF. Crocetin significantly suppressed VEGF-induced tube formation by HUVECs and migration of HRMECs. It also significantly inhibited phosphorylation of p38 and protected VE-cadherin expression. These findings indicate that crocetin suppresses the VEGF-induced angiogenesis by inhibiting migration and that the inhibition of phosphorylated-p38 and protection of VE-cadherin expression may be involved in its underlying mechanism of action.
authors.affiliation: Riken Vitamin Co., Ltd., 2-9-18 Misaki-cho, Tokyo 101-8370, Japan.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Umigai
authors.forename: Junji
authors.initials: J
authors.lastname: Tanaka
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsuruma
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Shimazawa
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D002338:Carotenoids / Q000494:pharmacology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000502:physiology; D014801:Vitamin A / Q000031:analogs & derivatives; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; C487773:trans-sodium crocetinate; D014801:Vitamin A; D002338:Carotenoids; D048051:p38 Mitogen-Activated Protein Kinases