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Am J Physiol Cell Physiol 297: C1263-C1274, 2009. First published August 26, 2009; doi:10.1152/ajpcell.00109.2009
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Receptors and Signal Transduction

Transforming growth factor-β1 downregulates caveolin-1 expression and enhances sphingosine 1-phosphate signaling in cultured vascular endothelial cells

Junsuke Igarashi,1 Kazuyo Shoji,2 Takeshi Hashimoto,1 Tetsuya Moriue,2 Kozo Yoneda,2 Tomoko Takamura,2 Tetsuo Yamashita,1 Yasuo Kubota,2 and Hiroaki Kosaka1

Department of 1Cardiovascular Physiology and 2Dermatology, Faculty of Medicine, Kagawa University, Kagawa, Japan

Submitted 10 March 2009 ; accepted in final form 26 August 2009

In vascular endothelial cells, specialized microdomains of plasma membrane termed caveolae modulate various receptor signal transduction pathways regulated by caveolin-1, a resident protein of caveolae. We examined whether transforming growth factor-β1 (TGF-β1), a multifunctional cytokine, alters expression levels of caveolin-1 and influences heterologous receptor signaling. Treatment of cultured bovine aortic endothelial cells (BAEC) with TGF-β1 induces marked decreases in caveolin-1 expression in a time- and dose-dependent fashion at both levels of protein and mRNA. A pharmacological inhibitor of activin receptor-like kinase 5 (ALK-5) counteracts caveolin-1 downregulation by TGF-β1, indicating the involvement of ALK-5 receptor subtype for TGF-β1. Sphingosine 1-phosphate (S1P) is a serum-borne angiogenic lipid growth factor that exerts a wide variety of biological actions. S1P modulates G protein-coupled S1P receptors, activating downstream molecules kinases AMP-activated protein kinase (AMPK), and Akt as well as a small G protein Rac1, ultimately to promote migration. Because S1P receptor signaling is associated with caveolae/caveolin-1, we examined whether pretreatment with TGF-β1 enhances effects of S1P on BAEC. Whereas S1P alone evokes robust BAEC responses to S1P, pretreatment with TGF-β1 leads to even higher magnitudes of S1P-elicited signaling responses and cell migration. Conversely, genetic knockdown of caveolin-1 using small interfering RNA mimics TGF-β1-induced promotion of BAEC responses to S1P. Collectively, these data demonstrate that TGF-β1 downregulates caveolin-1 of cultured endothelial cells, involving ALK-5 receptor subtype. Because downregulation of caveolin-1 by TGF-β1 promotes subsequent heterologous receptor signaling by S1P, these results may also identify novel point of cross-talk between cytokines and sphingolipids within endothelial signal transduction machineries.

cytokines; sphingolipids; G protein-coupled receptors; endothelium; signal transduction


Address for reprint requests and other correspondence: J. Igarashi, 1750-1 Ikenobe, Miki-Cho, Kita-Gun, Kagawa 761-0793, Japan (e-mail: igarashi{at}med.kagawa-u.ac.jp).






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