title: Neurotrophin production in brain pericytes during hypoxia: a role of pericytes for neuroprotection.
abstract: Neurotrophins are crucial regulators of neuronal survival and death. Evidence suggests that cells comprising the neurovascular unit (NVU) cooperatively mediate neuronal development, survival and regeneration. The aim of this study was to test whether cerebrovascular cells, endothelial cells and pericytes, produce neurotrophins and play neuroprotective roles during hypoxic insults. We examined the expression of neurotrophins and their receptors in cultured human cerebral microvascular endothelial cells and pericytes, astrocytes and the rat neuronal cell line PC12. Differentiated PC12 cells expressed TrkA, the NGF receptor, which was significantly upregulated by hypoxia at 1% O(2) and regulated neuronal survival. Both pericytes and astrocytes expressed three neurotrophins, i.e. NGF, BDNF and NT-3, while TrkB and TrkC, specific receptors for BDNF and NT-3, were expressed in astrocytes, but not pericytes. In response to hypoxia, among the neurotrophins expressed in pericytes and astrocytes only NT-3 expression was significantly upregulated in pericytes. Treatment of astrocytes with NT-3 significantly activated Erk1/2 and increased the expression of NGF both at mRNA and protein levels. The MEK1 inhibitor U0126 or siRNA-mediated knockdown of TrkC abolished the NT-3-induced upregulation of NGF in astrocytes. Taken together, cerebral microvascular pericytes and astrocytes are potent producers of neurotrophins in the NVU. In response to hypoxia, pericytes increase NT-3 production, which induces astrocytes to increase NGF production through the TrkC-Erk1/2 pathway. The interplay between pericytes and astrocytes through neurotrophins in the NVU may play an important role in neuronal survival under hypoxic conditions.
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ishitsuka
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ago
authors.forename: Koichi
authors.initials: K
authors.lastname: Arimura
authors.forename: Kuniyuki
authors.initials: K
authors.lastname: Nakamura
authors.forename: Himiko
authors.initials: H
authors.lastname: Tokami
authors.forename: Noriko
authors.initials: N
authors.lastname: Makihara
authors.forename: Junya
authors.initials: J
authors.lastname: Kuroda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kamouchi
authors.forename: Takanari
authors.initials: T
authors.lastname: Kitazono
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology; D001921:Brain / Q000378:metabolism*; D002454:Cell Differentiation; D017931:DNA Primers / Q000737:chemistry; D042783:Endothelial Cells / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia; D008833:Microcirculation; D009414:Nerve Growth Factors / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D020286:Pericytes / Q000378:metabolism*; D016133:Polymerase Chain Reaction / Q000379:methods; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D020812:Receptor, trkC / Q000378:metabolism; D013997:Time Factors
chemical_list: D017931:DNA Primers; D004791:Enzyme Inhibitors; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; D020812:Receptor, trkC