This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 23/2/231    most recent 01.ATV.0000052670.55321.87v1 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 Nakagawa, T. Articles by Sato, Y. Search for Related Content PubMed PubMed Citation Articles by Nakagawa, T. Articles by Sato, Y. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Genetics Home Reference Related Collections Angiogenesis Other Vascular biology

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:231.)
© 2003 American Heart Association, Inc.

Vascular Biology

HEX Acts as a Negative Regulator of Angiogenesis by Modulating the Expression of Angiogenesis-Related Gene in Endothelial Cells In Vitro

Tomowaki Nakagawa; Mayumi Abe; Tohru Yamazaki; Hiroki Miyashita; Hitoshi Niwa; Shoichi Kokubun; Yasufumi Sato

From the Department of Vascular Biology (T.N., M.A., T.Y., H.M., Y.S.), Institute of Development, Aging and Cancer, Tohoku University, Sendai; the Department of Orthopedic Surgery (T.N., S.K.), Tohoku University Graduate School of Medicine, Sendai; and the Laboratory for Cell Pluripotency Studies (H.N.), RIKEN Center for Developmental Biology, Kobe, Japan.

Correspondence to Yasufumi Sato, Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. E-mail y-sato{at}idac.tohoku.ac.jp

Objective— The hematopoietically expressed homeobox (HEX) is transiently expressed in endothelial cells (ECs) during vascular formation in embryo. Here, we investigated whether HEX played any role in angiogenesis-related properties of ECs in vitro.

Methods and Results— We transiently overexpressed HEX in human umbilical vein ECs (HUVECs). To our surprise, HEX completely abrogated the response of HUVECs to vascular endothelial growth factor (VEGF) with regard to proliferation, migration, and invasion and abolished network formation by HUVECs on Matrigel. cDNA microarray analysis and quantitative real-time reverse transcription–polymerase chain reaction combined with Western blotting revealed that HEX significantly repressed the expression of VEGF receptor-1, VEGF receptor-2, neuropilin-1, tyrosine kinase with Ig and EGF homology domains (TIE)-1, TIE-2, and the integrin v subunit, whereas it augmented the expression of endoglin in HUVECs. We established murine embryonic stem cells that were stably transfected with HEX sense cDNA or antisense cDNA, and we examined the in vitro differentiation to ECs. Although the expression of VEGF receptor-2 was decreased in sense transfectants, the number of cells expressing VE-cadherin, a specific marker of ECs, was not altered.

Conclusions— Our present results suggest that HEX may not affect the differentiation of ECs but acts as a negative regulator of angiogenesis.

Key Words: angiogenesis • HEX • transcription factor • endothelial cell

This article has been cited by other articles:

				Y. Chen and D. H. Gorski Regulation of angiogenesis through a microRNA (miR-130a) that down-regulates antiangiogenic homeobox genes GAX and HOXA5 Blood, February 1, 2008; 111(3): 1217 - 1226. [Abstract] [Full Text] [PDF]

				Y. Chen, A. D. Leal, S. Patel, and D. H. Gorski The Homeobox Gene GAX Activates p21WAF1/CIP1 Expression in Vascular Endothelial Cells through Direct Interaction with Upstream AT-rich Sequences J. Biol. Chem., January 5, 2007; 282(1): 507 - 517. [Abstract] [Full Text] [PDF]

				A. Hamik, B. Wang, and M. K. Jain Transcriptional Regulators of Angiogenesis Arterioscler. Thromb. Vasc. Biol., September 1, 2006; 26(9): 1936 - 1947. [Abstract] [Full Text] [PDF]

				T. Shibuya, K. Watanabe, H. Yamashita, K. Shimizu, H. Miyashita, M. Abe, T. Moriya, H. Ohta, H. Sonoda, T. Shimosegawa, et al. Isolation and Characterization of Vasohibin-2 as a Homologue of VEGF-Inducible Endothelium-Derived Angiogenesis Inhibitor Vasohibin Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 1051 - 1057. [Abstract] [Full Text] [PDF]

				A. Kubo, V. Chen, M. Kennedy, E. Zahradka, G. Q. Daley, and G. Keller The homeobox gene HEX regulates proliferation and differentiation of hemangioblasts and endothelial cells during ES cell differentiation Blood, June 15, 2005; 105(12): 4590 - 4597. [Abstract] [Full Text] [PDF]

				H. Hallaq, E. Pinter, J. Enciso, J. McGrath, C. Zeiss, M. Brueckner, J. Madri, H. C. Jacobs, C. M. Wilson, H. Vasavada, et al. A null mutation of Hhex results in abnormal cardiac development, defective vasculogenesis and elevated Vegfa levels Development, October 15, 2004; 131(20): 5197 - 5209. [Abstract] [Full Text] [PDF]

				T. E. Swingler, K. L. Bess, J. Yao, S. Stifani, and P.-S. Jayaraman The Proline-rich Homeodomain Protein Recruits Members of the Groucho/Transducin-like Enhancer of Split Protein Family to Co-repress Transcription in Hematopoietic Cells J. Biol. Chem., August 13, 2004; 279(33): 34938 - 34947. [Abstract] [Full Text] [PDF]

				T. Minami, T. Murakami, K. Horiuchi, M. Miura, T. Noguchi, J.-i. Miyazaki, T. Hamakubo, W. C. Aird, and T. Kodama Interaction between Hex and GATA Transcription Factors in Vascular Endothelial Cells Inhibits flk-1/KDR-mediated Vascular Endothelial Growth Factor Signaling J. Biol. Chem., May 14, 2004; 279(20): 20626 - 20635. [Abstract] [Full Text] [PDF]