Vascular endothelial cells synthesize and secrete brain‐derived neurotrophic factor

Nakahashi, Takeshi; Fujimura, Hironobu; Altar, C. Anthony; Li, Jess; Kambayashi, Jun-ichi; Tandon, Narendra N.; Sun, Bing

doi:10.1016/s0014-5793(00)01302-8

Cited by 396 publications

(268 citation statements)

References 31 publications

(30 reference statements)

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“…Neurotrophins (BDNF) have been shown to be expressed by some, but not all, endothelial cells in culture (6,8,43). Using brain-derived, immortalized endothelial cells (RBE4 cells) we determined that these cells indeed express BDNF in our threedimensional culture system and that expression is increased following hypoxic treatment (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In recent studies we and others have (3,4) shown that selected angiogenic factors, VEGF 1 in particular, are capable of not only affecting a variety of endothelial behaviors but also are capable of affecting neuronal behavior in a receptor-specific fashion. Interestingly, recent studies have demonstrated that neurotrophins expressed by endothelia and are capable of influencing several endothelial cell functions including endothelial cell survival and vessel stabilization (5)(6)(7) and that endothelial cells may express neurotrophin receptors (8).…”

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confidence: 99%

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Paracrine and Autocrine Functions of Brain-derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF) in Brain-derived Endothelial Cells

Kim

Hempstead

et al. 2004

Journal of Biological Chemistry

190

146

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Brain-derived neurotrophic factor (BDNF) is expressed by endothelial cells. We investigated the characteristics of BDNF expression by brain-derived endothelial cells and tested the hypothesis that BDNF serves paracrine and autocrine functions affecting the vasculature of the central nervous system. In addition to expressing TrkB and p75 NTR and BDNF under normoxic conditions, these cells increased their expression of BDNF under hypoxia. While the expression of TrkB is unaffected by hypoxia, TrkB exhibits a base-line phosphorylation under normoxic conditions and an increased phosphorylation when BDNF is added. TrkB phosphorylation is decreased when endogenous BDNF is sequestered by soluble TrkB. Exogenous BDNF elicits robust angiogenesis and survival in three-dimensional cultures of these endothelial cells, while sequestration of endogenous BDNF caused significant apoptosis. The effects of BDNF engagement of TrkB appears to be mediated via the phosphatidylinositol (PI) 3-kinase-Akt pathway. Modulation of BDNF levels directly correlate with Akt phosphorylation and inhibitors of PI 3-kinase abrogate the BDNF responses. BDNF-mediated effects on endothelial cell survival/apoptosis correlated directly with activation of caspase 3. These endothelial cells also express p75 NTR and respond to its preferred ligand, pro-nerve growth factor (pro-NGF), by undergoing apoptosis. These data support a role for neurotrophins signaling in the dynamic maintenance/differentiation of central nervous system endothelia.Angiogenesis is a tightly controlled process in which new vessels form from those pre-existing. This process occurs in a regulated fashion during development and growth as well as in response to physiological and pathological stimuli. Angiogenesis as been shown to be a receptor-and ligand-regulated process, with a still growing, diverse number of soluble factors and their cognate receptors being involved in the different phases of the angiogenic process (1). In the developing brain, angiogenesis has been shown to be regulated by factors secreted by neuronal and glial cell populations in an orderly, spatiotemporal fashion (2). In recent studies we and others have (3,4) shown that selected angiogenic factors, VEGF 1 in particular, are capable of not only affecting a variety of endothelial behaviors but also are capable of affecting neuronal behavior in a receptor-specific fashion. Interestingly, recent studies have demonstrated that neurotrophins expressed by endothelia and are capable of influencing several endothelial cell functions including endothelial cell survival and vessel stabilization (5-7)

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Paracrine and Autocrine Functions of Brain-derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF) in Brain-derived Endothelial Cells

Kim

Hempstead

et al. 2004

Journal of Biological Chemistry

190

146

View full text Add to dashboard Cite

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“…However, many immune and vascular endothelial cells also produce BNDF (Besser and Wank, 1999;Furuno and Nakanishi, 2006;Kerschensteiner et al, 1999;Kimata, 2005;Nakahashi et al, 2000;Prakash et al, 2009;Rezaee et al, 2010;Ziemssen et al, 2002); serum BDNF also correlates with leukocyte BDNF mRNA (Cattaneo et al, 2009), and systemic levels of BDNF are actually increased during attacks of multiple sclerosis (Liguori et al, 2009). Thus, there may be a complicated relationship between cortical and serum BDNF (Gass and Hellweg, 2010).…”

Section: Discussionmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor Serum Levels and Genotype: Association with Depression during Interferon-α Treatment

Lotrich

Albusaysi

Ferrell

2012

Neuropsychopharmacol

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Depression has been associated with inflammation, and inflammation may both influence and interact with growth factors such as brainderived neurotrophic factor (BDNF). Both the functional Val66Met BDNF polymorphism (rs6265) and BDNF levels have been associated with depression. It is thus plausible that decreased BDNF could mediate and/or moderate cytokine-induced depression. We therefore prospectively employed the Beck Depression Inventory-II (BDI-II), the Hospital Anxiety and Depression Scale (HADS), and the Montgomery-Asberg Depression Rating Scale (MADRS) in 124 initially euthymic patients during treatment with interferon-alpha (IFN-a), assessing serum BDNF and rs6265. Using mixed-effect repeated measures, lower pretreatment BDNF was associated with higher depression symptoms during IFN-a treatment (F 144,17.2 ¼ 6.8; Po0.0001). However, although the Met allele was associated with lower BDNF levels (F 1,83.0 ¼ 5.0; P ¼ 0.03), it was only associated with increased MADRS scores (F 4,8.9 ¼ 20.3; Po0.001), and not the BDI-II or HADS. An exploratory comparison of individual BDI-II items indicated that the Met allele was associated with suicidal ideation, sadness, and worthlessness, but not neurovegetative symptoms. Conversely, the serotonin transporter promoter polymorphism (5-HTTLPR) short allele was associated with neurovegetative symptoms such as insomnia, poor appetite and fatigue, but not sadness, worthlessness, or suicidal ideation. IFN-a therapy further lowered BDNF serum levels (F 4,37.7 ¼ 5.0; P ¼ 0.003), but this decrease occurred regardless of depression development. The findings thus do not support the hypothesis that decreasing BDNF is the primary pathway by which IFN-a worsens depression. Nonetheless, the results support the hypothesis that BDNF levels influence resiliency against developing inflammatory cytokine-associated depression, and specifically to a subset of symptoms distinct from those influenced by 5-HTTLPR. Neuropsychopharmacology (2013) 38, 985-995;

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“…The implantation of foam containing BDNF increased the number of blood vessels at the mid-level of the implant compared to the control foam at 8 weeks after implantation. Blood vessels are formed by endothelial cells, which produce and secrete BDNF [60]. Also, BNDF is a known survival factor for endothelial cells, which express the trkB receptor [61].…”

Section: Discussionmentioning

confidence: 99%

Freeze-dried poly(d,l-lactic acid) macroporous guidance scaffolds impregnated with brain-derived neurotrophic factor in the transected adult rat thoracic spinal cord

et al. 2004

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The effects of poly(D,L-lactic acid) macroporous guidance scaffolds (foams) with or without brain-derived neurotrophic factor (BDNF) on tissue sparing, neuronal survival, axonal regeneration, and behavioral improvements of the hindlimbs following implantation in the transected adult rat thoracic spinal cord were studied. The foams were embedded in fibrin glue containing acidic-fibroblast growth factor. One group of animals received fibrin glue with acidic-fibroblast growth factor only. The foams were prepared by a thermally induced polymer-solvent phase separation process and contained longitudinally oriented macropores connected to each other by a network of micropores. Both foams and fibrin only resulted in a similar gliotic and inflammatory response in the cord-implant interfaces. With BDNF foam, up to 20% more NeuN-positive cells in the spinal nervous tissue close to the rostral but not caudal spinal cord-implant interface survived than with control foam or fibrin only at 4 and 8 weeks after implantation. Semithin plastic sections and electron microcopy revealed that cells and axons more rapidly invaded BDNF foam than control foam. Also, BDNF foam contained almost twice as many blood vessels than control foam at 8 weeks after implantation. Tissue sparing was similar in all three implantation paradigms; approximately 42% of tissue was spared in the rostral cord and approximately 37% in the caudal cord at 8 weeks post grafting. The number of myelinated and unmyelinated axons was low and not different between the two types of foams. Many more axons were found in the fibrin only graft. Serotonergic axons were not found in any of the implants and none of the axons regenerated into the caudal spinal cord. The behavioral improvements in the hindlimbs were similar in all groups. These findings indicated that foam is well tolerated within the injured spinal cord and that the addition of BDNF promotes cell survival and angiogenesis. However, the overall axonal regeneration response is low. Future research should explore the use of poly(D,L-lactic acid) foams, with or without axonal growth-promoting factors, seeded with Schwann cells to enhance the axonal regeneration and myelination response.

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Vascular endothelial cells synthesize and secrete brain‐derived neurotrophic factor

Cited by 396 publications

References 31 publications

Paracrine and Autocrine Functions of Brain-derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF) in Brain-derived Endothelial Cells

Paracrine and Autocrine Functions of Brain-derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF) in Brain-derived Endothelial Cells

Brain-Derived Neurotrophic Factor Serum Levels and Genotype: Association with Depression during Interferon-α Treatment

Freeze-dried poly(d,l-lactic acid) macroporous guidance scaffolds impregnated with brain-derived neurotrophic factor in the transected adult rat thoracic spinal cord

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