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Communication Dans Un Congrès Année : 2017

Vasorelaxing effect of a TrkB receptor agonist on mesenteric arteries

Résumé

Introduction: Brain-derived neurotrophic factor (BDNF) is a neurotrophin unanimously recognized for its promoting effect on neuroplasticity and cognition, through activation of tropomyosin receptor kinase B (TrkB). In opposition with the traditional thinking that neurons are the main source of BDNF, endothelial cells were found to express large amounts of BDNF. Exogenous BDNF was reported to exert vasodilating properties on isolated pulmonary artery and aorta. However, whether peripheral vascular resistances are controlled by endothelial BDNF is not known. To address this question, we investigated the vasorelaxant properties and the underlying signaling pathways of a TrkB agonist (LM22A4) on mesenteric arteries in rat.Material and methods: Experiments were conducted on third-order mesenteric arteries harvested from 24 male Wistar rats (6–8 week-old) and mounted in isometric conditions. Intact or endothelium-denuded arteries were pre-constricted with phenylephrine (3 × 10−5 m) and relaxed with cumulative concentrations LM22A4 (10−11–10−4 m). Cyclotraxin B (10−6 m) was used as a TrkB antagonist. Vessels were also incubated with various specific inhibitors to assess the signaling pathways activated by LM22A4 including nitric oxide- (L-NAME, 10−4 m), endothelium-derived hyperpolarizing factor- (EDHF, apamin 10−7 m and charybdotoxin 10−7 m), PGI2- (U51605, 10−6 m), PI3K/Akt- (wortmannin 3 × 10−8 m), CaM/CaMKII (Calmidazolium 10−5 m, KN-62 10−5 m) and PLCγ- (U73122 10−5 m) dependent pathways.Results: Our results showed that LM22A4 induced vasorelaxation in mesenteric arteries, with maximal effect Emax 51 ± 7% and concentration for 50% of maximal effect (EC50) of approximately 0.025 μm. Endothelium removal as well as cyclotraxin B significantly blunted the effect of LM22A4. In addition, endothelium-dependent relaxant effect of LM22A4 was reduced by inhibitors of NO, EDHF, PGI2 production and PI3K/Akt signaling pathways. By contrast, vasodilating effect of LM22A4 was not modified by inhibition of CaM/CaMKII and PLCγ pathways.Discussion/Conclusion: In conclusion, our data demonstrated for the first time the capacity of a TrkB agonist to vasodilate peripheral resistance arteries. This effect involved activation of endothelial TrkB receptors and relied on production of NO, EDHF, PGI2 and activation of PI3K/Akt pathway. These data, combined with evidence that endothelial BDNF expression is decreased by hypertension and increased by physical training, suggest a possible role of BDNF in endothelial dysfunction.
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Dates et versions

hal-01565899 , version 1 (20-07-2017)

Identifiants

  • HAL Id : hal-01565899 , version 1

Citer

Perle Totoson, Christine Marie, C. Demougeot. Vasorelaxing effect of a TrkB receptor agonist on mesenteric arteries. Annual Meeting of French Society of Pharmacology and Therapeutics, and INSERM Clinical Research Centers(CIC) Meeting, Apr 2017, Rouen, France. pp.21-21 / PM1-005. ⟨hal-01565899⟩
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