Insulin-like growth factor I is required for vessel remodeling in the adult brain
1. C. Lopez-Lopez*,
2. D. LeRoith†, and
3. I. Torres-Aleman*,‡
1. *Laboratory of Neuroendocrinology, Cajal Institute, Consejo Superior de Investigaciones Cientifícas, 28002 Madrid, Spain; and †Clinical Endocrinology Branch, National Institutes of Health, Bethesda, MD 20892
1. Edited by Fred H. Gage, The Salk Institute for Biological Studies, San Diego, CA, and approved May 17, 2004 (received for review January 15, 2004)
Although vascular dysfunction is a major suspect in the etiology of several important neurodegenerative diseases, the signals involved in vessel homeostasis in the brain are still poorly understood. We have determined whether insulin-like growth factor I (IGF-I), a wide-spectrum growth factor with angiogenic actions, participates in vascular remodeling in the adult brain. IGF-I induces the growth of cultured brain endothelial cells through hypoxiainducible factor 1a and vascular endothelial growth factor, a canonical angiogenic pathway. Furthermore, the systemic injection of IGF-I in adult mice increases brain vessel density. Physical exercise that stimulates widespread brain vessel growth in normal mice fails to do so in mice with low serum IGF-I. Brain injury that stimulates angiogenesis at the injury site also requires IGF-I to promote perilesion vessel growth, because blockade of IGF-I input by an anti-IGF-I abrogates vascular growth at the injury site. Thus, IGF-I participates in vessel remodeling in the adult brain. Low serum/brain IGF-I levels that are associated with old age and with several neurodegenerative diseases may be related to an increased risk of vascular dysfunction.
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• This paper was submitted directly (Track II) to the PNAS office.
• Abbreviations: IGF-I, insulin-like growth factor I; HIF-1a, hypoxia-inducible factor 1a; DN-HIF-1a, dominant negative HIF-1a; VEGF, vascular endothelial growth factor; VEGFR1 and -2, VEGFR receptors 1 and 2; LID, liver IGF-I-deleted; NRS, nonimmune rabbit serum.
• Copyright © 2004, The National Academy of Sciences