[Vasorin is a potential therapeutic target for vascular fibroproliferative disorders]
>>Published online before print July 9, 2004
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0404117101
Medical Sciences
Vasorin, a transforming growth factor -binding protein expressed in vascular smooth muscle cells, modulates the arterial response to injury in vivo
Yuichi Ikeda *, Yasushi Imai , Hidetoshi Kumagai *, Tetsuya Nosaka *, Yoshihiro Morikawa ¶, Tomoko Hisaoka ¶, Ichiro Manabe , Koji Maemura , Takashi Nakaoka ||, Takeshi Imamura **, Kohei Miyazono , Issei Komuro , Ryozo Nagai , and Toshio Kitamura *
Divisions of *Hematopoietic Factors and Cellular Therapy and ||Department of Advanced Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; Departments of Cardiovascular Medicine and Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan; Takada Research Laboratories, Chugai Pharmaceutical Company, Limited, Tokyo 171-8545, Japan; ¶Department of Anatomy and Neurobiology, Wakayama Medical School, Wakayama 641-8509, Japan; **Department of Biochemistry, Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo 170-8455, Japan; and Department of Cardiovascular Science and Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
Communicated by Masashi Yanagisawa, University of Texas Southwestern Medical Center, Dallas, TX, June 9, 2004 (received for review February 25, 2004)
Growth factors, cell-surface receptors, adhesion molecules, and extracellular matrix proteins play critical roles in vascular pathophysiology by affecting growth, migration, differentiation, and survival of vascular cells. In a search for secreted and cell-surface molecules expressed in the cardiovascular system, by using a retrovirus-mediated signal sequence trap method, we isolated a cell-surface protein named vasorin. Vasorin is a typical type I membrane protein, containing tandem arrays of a characteristic leucine-rich repeat motif, an epidermal growth factor-like motif, and a fibronectin type III-like motif at the extracellular domain. Expression analyses demonstrated that vasorin is predominantly expressed in vascular smooth muscle cells, and that its expression is developmentally regulated. To clarify biological functions of vasorin, we searched for its binding partners and found that vasorin directly binds to transforming growth factor (TGF)- and attenuates TGF- signaling in vitro. Vasorin expression was down-regulated during vessel repair after arterial injury, and reversal of vasorin down-regulation, by using adenovirus-mediated in vivo gene transfer, significantly diminished injury-induced vascular lesion formation, at least in part, by inhibiting TGF- signaling in vivo. These results suggest that down-regulation of vasorin expression contributes to neointimal formation after vascular injury and that vasorin modulates cellular responses to pathological stimuli in the vessel wall. Thus, vasorin is a potential therapeutic target for vascular fibroproliferative disorders.<<
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