Insulin-like growth factor 1 (IGF-1) is a peptide hormone that circulates in the blood in complex with insulin-like growth factor binding proteins (IGFBPs), usually IGFBP-3. IGF-1 has multiple effects in the brain, including promoting vessel remodeling. Nishijima et al. explored the regulation and mechanisms of IGF-1 transport across the blood-brain barrier (BBB). In rats injected with human recombinant IGF-1 (hIGF-1), increased concentrations of hIGF-1 were detected in electrically stimulated, but not unstimulated, brain regions. Unilateral whisker stimulation caused increases in hIGF-1 concentrations and in tyrosine phosphorylation of the IGF-1 receptor in the somatosensory cortex, whereas the activation of neurons in the somatosensory cortex was reduced by the IGF-1 receptor antagonist PPP. Whisker stimulation increased cerebral blood flow in the somatosensory cortex, and inhibition of vasodilation blocked the increase in IGF-1 concentrations elicited by whisker stimulation. A two-chamber culture system was used to approximate the cellular organization of the BBB: The upper chamber contained endothelial cells cultured on a layer of astrocytes on a permeable membrane, and the lower chamber contained neurons. hIGF-1 added to the upper chamber was detected in neurons, presumably because of transcytosis by endothelial cells. Endocytosis of hIGF-1 by endothelial cells was decreased by the addition of IGFBP-3 to the upper chamber and increased by the addition of matrix metalloproteinase-9 (MMP-9), a protease that cleaves IGFBP-3, to the upper chamber. The increase in hIGF-1 concentrations elicited by whisker stimulation was blocked by the infusion of an MMP-9 inhibitor into the somatosensory cortex. Glutamate released from neurons has been proposed to trigger the release of vasodilators from astrocytes, such as ATP, prostaglandin E2 (PGE2), or 11, 12 epoxyeicosatrienoic acid (EET). Addition of glutamate to the lower chamber increased transcytosis of hIGF-1, an effect that was blocked by an MMP-9 inhibitor, and glutamate increased MMP-9 activity in endothelial-astrocyte cocultures. Transcytosis of IGF-1 by endothelial cells in the two-chamber culture system was increased by ATP, PGE2, or EET in an MMP-9–dependent manner. IGFBP-3 interacts with lipoprotein-related protein 1 (LRP1), and transfection of small interfering RNAs directed against LRP1 resulted in decreased internalization of hIGF-1 by endothelioma cells. The authors propose that neuronal activity increases vasodilation and MMP-9 activity in the endothelial cells of the BBB, thereby promoting the transport of IGF-1 from the circulation into the brain, possibly through an LRP1-dependent process.
T. Nishijima, J. Piriz, S. Duflot, A. M. Fernandez, G. Gaitan, U. Gomez-Pinedo, J. M. Garcia Verdugo, F. Leroy, H. Soya, A. Nuñez, I. Torres-Aleman, Neuronal activity drives localized blood-brain-barrier transport of serum insulin-like growth factor-I into the CNS. Neuron 67, 834–846 (2010). [PubMed]