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Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-? in cerebral microvessels.

ABSTRACT: We tested hypothesis that activation of the prostacyclin (PGI₂) receptor (IP receptor) signaling pathway in cerebral microvessels plays an important role in the metabolism of amyloid precursor protein (APP). In human brain microvascular endothelial cells activation of IP receptor with the stable analogue of PGI₂, iloprost, stimulated expression of amyloid precursor protein and a disintegrin and metalloprotease 10 (ADAM10), resulting in an increased production of the neuroprotective and anticoagulant molecule, soluble APP? (sAPP?). Selective agonist of IP receptor, cicaprost, and adenylyl cyclase activator, forskolin, also enhanced expression of amyloid precursor protein and ADAM10. Notably, in cerebral microvessels of IP receptor knockout mice, protein levels of APP and ADAM10 were reduced. In addition, iloprost increased protein levels of peroxisome proliferator-activated receptor ? (PPAR?) in human brain microvascular endothelial cells. PPAR?-siRNA abolished iloprost-augmented protein expression of ADAM10. In contrast, GW501516 (a selective agonist of PPAR?) upregulated ADAM10 and increased production of sAPP?. Genetic deletion of endothelial PPAR? (ePPAR?^-/-) in mice significantly reduced cerebral microvascular expression of ADAM10 and production of sAPP?. In vivo treatment with GW501516 increased sAPP? content in hippocampus of wild type mice but not in hippocampus of ePPAR?^-/- mice. Our findings identified previously unrecognized role of IP-PPAR? signal transduction pathway in the production of sAPP? in cerebral microvasculature.

SUBMITTER: He T

PROVIDER: S-EPMC5363732 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-α in cerebral microvessels.

He Tongrong T Santhanam Anantha Vijay R AV Lu Tong T d'Uscio Livius V LV Katusic Zvonimir S ZS

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20151120 1

We tested hypothesis that activation of the prostacyclin (PGI<sub>2</sub>) receptor (IP receptor) signaling pathway in cerebral microvessels plays an important role in the metabolism of amyloid precursor protein (APP). In human brain microvascular endothelial cells activation of IP receptor with the stable analogue of PGI<sub>2</sub>, iloprost, stimulated expression of amyloid precursor protein and a disintegrin and metalloprotease 10 (ADAM10), resulting in an increased production of the neuropr ...[more]

PMID: 26661245

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Project description:The role of brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B, in control of cerebral circulation is poorly understood. The present study was designed to investigate the cerebral vascular effects of BDNF in vivo.Replication incompetent adenovirus encoding either rat BDNF (AdBDNF) or green fluorescent protein was injected intracisternally into rabbits. Forty-eight hours later, animals were euthanized. Plasma and cerebrospinal fluid levels of BDNF were measured by enzyme-linked immunosorbent assay, vasomotor function of isolated basilar arteries was studied in organ chambers, protein expression in the basilar arteries was studied by Western blotting, prostanoid levels were measured by enzyme-linked immunosorbent assay, and cyclic adenosine 3',5'-monophosphate levels were measured by radioimmunoassay.The levels of BDNF in the cerebrospinal fluid were significantly elevated in AdBDNF-treated rabbits as compared with adenovirus encoding green fluorescent protein-treated rabbits (37+/-5 ng/mL versus 0.006+/-0.003 ng/mL, respectively; P<0.05; n=14). Western blotting studies revealed that in basilar arteries, AdBDNF increased protein expression of prostacyclin synthase, whereas expression of endothelial nitric oxide synthase and phosphorylated (Ser 1177) endothelial nitric oxide synthase remained unchanged. During incubation with arachidonic acid (1 micromol/L), PGI(2) production and levels of cyclic adenosine 3',5'-monophosphate were significantly elevated only in AdBDNF-treated rabbit basilar arteries (P<0.05, n=6). Relaxations to acetylcholine (10(-9) to 10(-5) mol/L) and arachidonic acid (10(-9) to 10(-5) mol/L) were significantly potentiated in basilar arteries from rabbits injected with AdBDNF. Potentiation of relaxations to acetylcholine in AdBDNF-treated basilar arteries was inhibited by the nonselective cyclooxygenase inhibitor, indomethacin (10(-5) mol/L, P<0.05, n=6) and constitutive phospholipase A(2) inhibitor, AACOCF3 (2x10(-5) mol/L, P<0.05, n=5).Our results demonstrate that in cerebral arteries, BDNF-induced activation of tropomyosin receptor kinase B receptor signaling in vivo promotes prostacyclin biosynthesis. These findings provide novel mechanistic insight into the vascular protective effect of BDNF in cerebral circulation.

Project description:BackgroundEndothelial cells (ECs) in cerebral vessels are considered the primary targets in acute hemorrhagic brain injuries. EC dysfunction can aggravate neuronal injuries by causing secondary inflammatory responses and blood-brain barrier (BBB) disruption. Previous studies have reported that enhancement of mitochondrial function within ECs may reduce BBB disruption and decrease the severity of acute brain injuries. However, the molecular signaling pathways through which enhanced EC mitochondrial function is enhanced to exert this BBB protective effect have not been fully elucidated.MethodsTo identify signaling pathways involved in linking EC-specific mitochondrial dysfunction and BBB disruption, we first performed RNA sequencing using isolated cerebral vessels from TEKCRIF1 KO mice, a mouse strain that displays EC-specific mitochondrial dysfunction. After identification, we assessed the significance of candidate signaling pathways using an intracerebral hemorrhage (ICH) mouse model. BBB integrity was assessed using an IgG leakage assay, and symptomatic changes were evaluated using behavioral assays.ResultsTranscriptome analyses of the TEKCRIF1 KO mouse revealed significant changes in Notch1 signaling, a pathway intimately involved in BBB maintenance. We also observed a decrease in Notch1 signaling and expression of the mitochondrial oxidative phosphorylation (OxPhos) complex in the ICH mouse model, which also exhibits BBB disruption. To further assess the function of Notch1 signaling in relation to BBB disruption, we injected ICH model mice with adropin, a protein that interacts with the Notch1 ligand NB-3 and activates Notch1 signaling. We found that adropin prevented BBB disruption and reduced the extent (area) of the injury compared with that in vehicle controls, in association with alteration of mitochondrial function.ConclusionThese results suggest that the Notch1 signaling pathway acts as an upstream regulator of DEGs and can be a target to regulate the changes involved with endothelial mitochondrial dysfunction-dependent BBB disruption. Thus, treatment methods that activate Notch1 may be beneficial in acute brain injuries by protecting BBB integrity.

Dataset Information

Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-? in cerebral microvessels.

Publications

Role of prostacyclin signaling in endothelial production of soluble amyloid precursor protein-α in cerebral microvessels.

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