Internalization of basic fibroblast growth factor at the mouse blood–brain barrier involves perlecan, a heparan sulfate proteoglycan

Deguchi, Yoshiaki; Okutsu, Hiroshi; Okura, Takashi; Yamada, Shizuo; Kimura, Ryohei; Yuge, Takuro; Furukawa, Akihiko; Morimoto, Kazuhiro; Tachikawa, Masanori; Ohtsuki, Sumio; Hosoya, Ken

doi:10.1046/j.1471-4159.2002.01129.x

Cited by 61 publications

(34 citation statements)

References 29 publications

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“…This finding is also consistent with a recent study, which showed that the uptake of the basic fibroblast growth factor by the BBB is greatly enhanced by cell surface HSPGs (21). Interestingly, Argyris et al, by using a method similar to ours, also found that the removal of both HSPGs and CSPGs reduces HIV-1 entry into BMECs (8).…”

Section: Discussionsupporting

confidence: 93%

Contribution of Proteoglycans to Human Immunodeficiency Virus Type 1 Brain Invasion

Bobardt

Salmon

Wang

et al. 2004

J Virol

106

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As a neurotropic virus, human immunodeficiency virus type 1 (HIV-1) invades the brain and causes severe neuronal, astrocyte, and myelin damage in AIDS patients. To gain access to the brain, HIV-1 must migrate through brain microvascular endothelial cells (BMECs), which compose the blood-brain barrier (BBB). Given that BMECs lack the entry receptor CD4, HIV-1 must use receptors distinct from CD4 to enter these cells. We previously reported that cell surface proteoglycans serve as major HIV-1 receptors on primary human endothelial cells. In this study, we examined whether proteoglycans also impact cell-free HIV-1 invasion of the brain. Using an artificial BBB transmigration assay, we found that both heparan and chondroitin sulfate proteoglycans (HSPGs and CSPGs, respectively) are abundantly expressed on primary BMECs and promote HIV-1 attachment and entry. In contrast, the classical entry receptors, CXCR4 and CCR5, only moderately enhanced these processes. HSPGs and CSPGs captured HIV-1 in a gp120-dependent manner. However, no correlation between coreceptor usage and transmigration was identified. Furthermore, brain-derived viruses did not transmigrate more efficiently than lymphoid-derived viruses, suggesting that the ability of HIV-1 to replicate in the brain does not correlate with its capacity to migrate through the BBB as cell-free virus. Given that HIV-1-proteoglycan interactions are based on electrostatic contacts between basic residues in gp120 and sulfate groups in proteoglycans, HIV-1 may exploit these interactions to rapidly enter and migrate through the BBB to invade the brain.

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Section: Discussionsupporting

confidence: 93%

Contribution of Proteoglycans to Human Immunodeficiency Virus Type 1 Brain Invasion

Bobardt

Salmon

Wang

et al. 2004

J Virol

106

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“…It has been reported that FGFR-1 internalization peaks within 45 minutes after stimulation. 24 Thus, binding to its specific receptor and receptor internalization might contribute to the decrease of bFGF in the heparin-exchangeable bFGF fraction.…”

Section: Discussionmentioning

confidence: 99%

Thrombin- and Factor Xa–Induced DNA Synthesis Is Mediated by Transactivation of Fibroblast Growth Factor Receptor-1 in Human Vascular Smooth Muscle Cells

Rauch

Millette

Kenagy

et al. 2004

Circulation Research

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Abstract-Thrombin and factor Xa (FXa) are agonists for G protein-coupled receptors (GPRCs) and may contribute to vascular lesion formation by stimulating proliferation of vascular smooth muscle cells (SMCs). Mitogenic signaling of GPCRs requires transactivation of receptor tyrosine kinases (RTKs). In rat SMCs, thrombin transactivates the epidermal growth factor receptor (EGFR) via a pathway that involves heparin-binding EGF-like growth factor (HB-EGF) as ligand for EGFR. The purpose of this study was to investigate in human SMCs the role of receptor transactivation in the mitogenic response to thrombin and FXa. Thrombin (10 nmol/L) and FXa (100 nmol/L) cause a 3.3-and 2.6-fold increase in DNA synthesis, respectively. In human SMCs, neither thrombin nor FXa causes EGFR phosphorylation, and blockade of EGFR kinase does not inhibit DNA synthesis. However, DNA synthesis and phosphorylation of fibroblast growth factor receptor-1 (FGFR-1) induced by thrombin or FXa are inhibited by antibodies neutralizing basic fibroblast growth factor (bFGF) or by heparin. Hirudin inhibits thrombin-, but not FXa-induced mitogenesis, indicating that FXa acts independently of thrombin. We further demonstrate by ELISA that upon thrombin and FXa stimulation, bFGF is released and binds to the extracellular matrix. Our data suggest that in human vascular SMCs, both thrombin and FXa rapidly release bFGF into the pericellular matrix. This is followed by transactivation of the FGFR-1 and increased proliferation. Heparin may inhibit the mitogenic effects of thrombin and Key Words: thrombin Ⅲ factor Xa Ⅲ basic fibroblast growth factor Ⅲ fibroblast growth factor receptor-1 Ⅲ epidermal growth factor receptor V ascular smooth muscle cell (SMC) proliferation and migration are key events in atherosclerosis and restenosis after vascular injury. 1,2 Mitogenic signaling of G proteincoupled receptors (GPCRs) involves transactivation of receptor tyrosine kinases (RTKs). 3 In several cell lines, it has been shown that the GPCR agonist thrombin mediates cell proliferation through transactivating the epidermal growth factor receptor (EGFR) via a metalloproteinase-mediated cleavage and release of pro-heparin binding EGF-like factor (HB-EGF), which then binds to EGFR. 3 We have shown that this mechanism is present in rat SMCs and is required for thrombin-induced migration. 4 Heparin, which inhibits SMC proliferation and migration in vivo and in vitro, 5-7 binds HB-EGF and interferes with this pathway. 4 We have investigated the possible role of receptor transactivation in the proliferation of human SMCs mediated by thrombin and the activated coagulation factor X (FXa). FXa is a serine protease that in addition to cleaving prothrombin activates thrombin receptors (protease-activated receptors, PARs), which are members of the GPCR family. 8 FXa acts as a thrombinindependent mitogen, 9,10 which is also sensitive to heparin inhibition. 11 In this study, we demonstrate that proliferation of human SMCs induced by thrombin and FXa does not involve EGFR transactivati...

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“…With respect to the brain pathology, it is likely that FGF-2 levels in serum resemble levels in the brain since this growth factor can cross the blood-brain barrier. 76,77 FGF-2 has been implicated in neurogenesis and gliogenesis during development as well as in adulthood [78][79][80][81] via its role as a neurotrophic factor. This is consistent with our findings of a strong PCP effect on the hippocampal proteome and metabonome, with respect to the number of molecular changes.…”

Section: Discussionmentioning

confidence: 99%

Hippocampal Proteomic and Metabonomic Abnormalities in Neurotransmission, Oxidative Stress, and Apoptotic Pathways in a Chronic Phencyclidine Rat Model

et al. 2015

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Schizophrenia is a neuropsychiatric disorder affecting 1% of the world's population. Due to a broad range of symptoms and wide heterogeneity, current therapeutic approaches in schizophrenia fail to treat all symptomatic manifestations of the disease. Therefore, new models that reproduce core pathological features of schizophrenia are needed for the elucidation of unidentified pathological disease mechanisms. Here, we employ a comprehensive global label-free liquid chromatographymass spectrometry (LC-MS) proteomic and metabonomic profiling analysis combined with targeted proteomics (selected reaction monitoring and multiplex-immunoassay) of serum and brain tissues from a chronic phencyclidine (PCP) rat model, in which NMDA-receptor hypofunction is induced through non-competitive N-methyl-D-aspartate (NMDA) antagonism. Using multiplex immunoassay, we identified serum abnormalities in cytokines (IL-5, IL-2, IL-1β) and the fibroblast-growth factor-2 levels, as peripheral biomarkers of PCP treatment. In order to find potential novel drug targets and to elucidate the pathways associated with the disease, extensive proteomic and metabonomic brain tissue profiling was employed. This revealed a more prominent effect of chronic PCP treatment on the hippocampal proteome and metabonome compared to the frontal cortex. Bioinformatic pathway analysis confirmed the abnormalities in NMDA-receptor associated pathways in both brain regions, as well as alterations in other neurotransmitter systems such as kainate, AMPA and GABAergic signalling in the hippocampus. Metabonomic profiling revealed changes in phospho-and glycolipids, which was further supported by findings of oxidative stress (superoxide dismutase) on the protein level. These molecular changes parallel findings observed in human schizophrenia. The present study could lead to increased understanding of how perturbed glutamate receptor signalling affects other relevant biological pathways in schizophrenia and therefore support drug discovery efforts for improved treatment of patients suffering from this debilitating psychiatric disorder.

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Internalization of basic fibroblast growth factor at the mouse blood–brain barrier involves perlecan, a heparan sulfate proteoglycan

Cited by 61 publications

References 29 publications

Contribution of Proteoglycans to Human Immunodeficiency Virus Type 1 Brain Invasion

Contribution of Proteoglycans to Human Immunodeficiency Virus Type 1 Brain Invasion

Thrombin- and Factor Xa–Induced DNA Synthesis Is Mediated by Transactivation of Fibroblast Growth Factor Receptor-1 in Human Vascular Smooth Muscle Cells

Hippocampal Proteomic and Metabonomic Abnormalities in Neurotransmission, Oxidative Stress, and Apoptotic Pathways in a Chronic Phencyclidine Rat Model

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