title: Dexamethasone induces caveolin-1 in vascular endothelial cells: implications for attenuated responses to VEGF.
abstract: Steroids exert direct actions on cardiovascular cells, although underlying molecular mechanisms remain incompletely understood. We examined if steroids modulate abundance of caveolin-1, a regulatory protein of cell-surface receptor pathways that regulates the magnitudes of endothelial response to vascular endothelial growth factor (VEGF). Dexamethasone, a synthetic glucocorticoid, induces caveolin-1 at both levels of protein and mRNA in a time- and dose-dependent manner in pharmacologically relevant concentrations in cultured bovine aortic endothelial cells. Aldosterone, a mineralocorticoid, but not the sex steroids 17β-estradiol, testosterone, or progesterone, elicits similar caveolin-1 induction. Caveolin-1 induction by dexamethasone and that by aldosterone were abrogated by RU-486, an inhibitor of glucocorticoid receptor, and by spironolactone, a mineralocorticoid receptor inhibitor, respectively. Dexamethasone attenuates VEGF-induced responses at the levels of protein kinases Akt and ERK1/2, small-G protein Rac1, nitric oxide production, and migration. When induction of caveolin-1 by dexamethasone is attenuated either by genetically by transient transfection with small interfering RNA or pharmacologically by RU-486, kinase responses to VEGF are rescued. Dexamethasone also increases expression of caveolin-1 protein in cultured human umbilical vein endothelial cells, associated with attenuated tube formation responses of these cells when cocultured with normal fibroblasts. Immunohistochemical analyses revealed that intraperitoneal injection of dexamethasone induces endothelial caveolin-1 protein in thoracic aorta and in lung artery in healthy male rats. Thus steroids functionally attenuate endothelial responses to VEGF via caveolin-1 induction at the levels of signal transduction, migration, and tube formation, identifying a novel point of cross talk between nuclear and cell-surface receptor signaling pathways.
authors: Department of Cardiovascular Physiology, Kagawa University, Kagawa, Japan. igarashi@med.kagawa-u.ac.jp
authors: Junsuke
authors: J
authors: Igarashi
authors: Takeshi
authors: T
authors: Hashimoto
authors: Kazuyo
authors: K
authors: Shoji
authors: Kozo
authors: K
authors: Yoneda
authors: Ikuko
authors: I
authors: Tsukamoto
authors: Tetsuya
authors: T
authors: Moriue
authors: Yasuo
authors: Y
authors: Kubota
authors: Hiroaki
authors: H
authors: Kosaka
mesh_terms: D000818:Animals; D002417:Cattle; D051242:Caveolin 1 / Q000096:biosynthesis*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D003907:Dexamethasone