This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gaetano, C. Articles by Capogrossi, M. C. Search for Related Content PubMed PubMed Citation Articles by Gaetano, C. Articles by Capogrossi, M. C. Related Collections Angiogenesis Gene regulation Growth factors/cytokines

(Circulation Research. 2001;88:e38.)
© 2001 American Heart Association, Inc.

UltraRapid Communication

Retinoids Induce Fibroblast Growth Factor-2 Production in Endothelial Cells via Retinoic Acid Receptor Activation and Stimulate Angiogenesis In Vitro and In Vivo

Carlo Gaetano¹, Alfonso Catalano¹, Barbara Illi, Angelina Felici, Saverio Minucci, Roberta Palumbo, Francesco Facchiano, Antonella Mangoni, Salvatore Mancarella, Judith Mühlhauser, Maurizio C. Capogrossi

From the Laboratorio di Patologia Vascolare (C.G., A.C., B.I., A.F., R.P., F.F., A.M., S.M., J.M., M.C.C.), Istituto Dermopatico dell’Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy; Sezione di Patologia Clinica (A.C.), Dipartimento di Oncologia e Neuroscienze, Facoltà di Medicina e Chirurgia, Università "G. D’Annunzio", Chieti, Italy; and Dipartimento di Oncologia Sperimentale (S.M.), Istituto Oncologico Europeo, Milan, Italy.

Correspondence to Dr Carlo Gaetano, Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, Via dei Monti di Creta, 104, 00167 Rome, Italy. E-mail gaetano{at}idi.it

Abstract—The effect of retinoic acid (RA) on endothelial cells is still controversial and was examined in the present study. In bovine aortic endothelial cells (BAECs), all-trans RA (ATRA) and 9-cis RA (9CRA), but not 13-cis RA (13CRA), induced fibroblast growth factor-2 (FGF-2) production and exhibited a biphasic dose-dependent effect to enhance BAEC proliferation and differentiation into tubular structures on reconstituted basement membrane proteins (Matrigel); both processes were inhibited by FGF-2–neutralizing antibody. The pan RA receptor (RAR)-selective ligand (E)-4-[2-(5,5,8,8,-tetramethyl-5,6,7,8-tetrahydro-2-naphtalenyl)-1-propenyl] benzoic acid and the RAR-selective ligand 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphtyl)-ethenyl] benzoic acid stimulated the production of FGF-2, whereas the addition of the RAR-antagonist RO 41-5253 inhibited this effect. In BAECs, the forced expression of RAR, but not RARß or RAR, enhanced FGF-2 production, whereas the RAR-dominant negative, 403, blocked this effect. Furthermore, RAR overexpression directly stimulated BAEC differentiation on Matrigel and potentiated the effects of ATRA in this assay. Finally, ATRA-treated BAECs coinjected with Matrigel subcutaneously in mice induced neovascularization within the Matrigel plug, and ATRA also enhanced angiogenesis in the chicken chorioallantoic membrane assay. In conclusion, RA can stimulate endothelial cell proliferation and differentiation in vitro via enhanced RAR-dependent FGF-2 production, and it can also induce angiogenesis in vivo. The full text of this article is available at http://www.circresaha.org.

Key Words: endothelial cell • angiogenesis • retinoic acid • retinoic acid receptor • fibroblast growth factor-2

This article has been cited by other articles:

				A. Uruno, A. Sugawara, H. Kanatsuka, H. Kagechika, A. Saito, K. Sato, M. Kudo, K. Takeuchi, and S. Ito Upregulation of Nitric Oxide Production in Vascular Endothelial Cells by All-trans Retinoic Acid Through the Phosphoinositide 3-Kinase/Akt Pathway Circulation, August 2, 2005; 112(5): 727 - 736. [Abstract] [Full Text] [PDF]

				K. Takamura, Y. Nasuhara, M. Kobayashi, T. Betsuyaku, Y. Tanino, I. Kinoshita, E. Yamaguchi, S. Matsukura, R. P. Schleimer, and M. Nishimura Retinoic acid inhibits interleukin-4-induced eotaxin production in a human bronchial epithelial cell line Am J Physiol Lung Cell Mol Physiol, April 1, 2004; 286(4): L777 - L785. [Abstract] [Full Text] [PDF]

				S. Ghatpande, A. Ghatpande, J. Sher, M. H. Zile, and T. Evans Retinoid signaling regulates primitive (yolk sac) hematopoiesis Blood, April 1, 2002; 99(7): 2379 - 2386. [Abstract] [Full Text] [PDF]