Vascular endothelial growth factor enhances profibrotic activities through modulation of calcium homeostasis in human atrial fibroblasts.
Lab Invest
; 100(2): 285-296, 2020 02.
Article
en En
| MEDLINE
| ID: mdl-31748680
ABSTRACT
Vascular endothelial growth factor (VEGF), a pivotal activator of angiogenesis and calcium (Ca2+) signaling in endothelial cells, was shown to increase collagen production in atrial fibroblasts. In this study, we evaluated whether VEGF may regulate Ca2+ homeostasis in atrial fibroblasts and contribute to its profibrogenesis. Migration, and proliferation analyses, patch-clamp assay, Ca2+ fluorescence imaging, and western blotting were performed using VEGF-treated (300 pg/mL or 1000 pg/mL) human atrial fibroblasts with or without coadministration of Ethylene glycol tetra-acetic acid (EGTA, 1 mmol/L), or KN93 (a Ca2+/calmodulin-dependent protein kinase II [CaMKII] inhibitor, 10 µmol/L). VEGF (1000 pg/mL) increased migration, myofibroblast differentiation, pro-collagen type I, pro-collagen type III production, and phosphorylated VEGF receptor 1 expression of fibroblasts. VEGF (1000 pg/mL) increased the nonselective cation current (INSC) of transient receptor potential (TRP) channels and potassium current of intermediate-conductance Ca2+-activated K+ (KCa3.1) channels thereby upregulating Ca2+ entry. VEGF upregulated phosphorylated ERK expression. An ERK inhibitor (PD98059, 50 µmol/L) attenuated VEGF-activated INSC of TRP channels. The presence of EGTA attenuated the profibrotic effects of VEGF on pro-collagen type I, pro-collagen type III production, myofibroblast differentiation, and migratory capabilities of fibroblasts. VEGF upregulated the expression of phosphorylated CaMKII in fibroblasts, which was attenuated by EGTA. In addition, KN93 reduced VEGF-increased pro-collagen type I, pro-collagen type III production, myofibroblast differentiation, and the migratory capabilities of fibroblasts. In conclusion, we found that VEGF increases atrial fibroblast activity through CaMKII signaling by enhancing Ca2+ entry. Our findings provide benchside evidence leading to a potential novel strategy targeting atrial myopathy and arrhythmofibrosis.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Fibrosis
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Calcio
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Factor A de Crecimiento Endotelial Vascular
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Fibroblastos
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Atrios Cardíacos
Límite:
Humans
Idioma:
En
Año:
2020
Tipo del documento:
Article