Vascular endothelial growth factor on Runt-related transcript factor-2 in aortic valve cells

Eur J Clin Invest. 2021 May;51(5):e13470. doi: 10.1111/eci.13470. Epub 2020 Dec 18.

Abstract

Background: Calcific aortic valve disease is associated with ageing and high mortality. However, no effective pharmacological treatment has been developed. Vascular endothelial growth factor (VEGF) and its receptor are overexpressed in the calcified aortic valve tissue. However, the role of VEGF in calcific aortic valve disease pathogenesis and its underlying mechanisms remain unclear.

Materials and methods: Runt-related transcription factor 2 expression and calcium-related signalling were investigated in porcine valvular interstitial cells with or without human VEGF-A recombinant protein (VEGF165 , 1-100 ng/mL) treatment and/or calmodulin-dependent kinase II (CaMKII) inhibitor (KN93, 10 µmol/L) and inositol triphosphate receptor inhibitor (2-aminoethyldiphenyl borate, 30 µmol/L) for 5 days.

Results: VEGF165 -treated cells had higher Runt-related transcription factor 2 expression and CaMKII/ adenosine 3',5'-monophosphate response element-binding protein (CREB) signalling activation than did control cells. KN93 reduced Runt-related transcription factor 2 expression and CREB phosphorylation in VEGF165 -treated cells. The 2-aminoethyldiphenyl borate also reduced Runt-related transcription factor 2 expression in VICs treated with VEGF165 .

Conclusion: VEGF upregulated Runt-related transcription factor 2 expression in VICs by activating the IP3R/CaMKII/CREB signalling pathway.

Keywords: calcific aortic valve disease; calmodulin-dependent kinase II; osteogenesis; runt-related transcription factor 2; vascular endothelial growth factor.

MeSH terms

  • Animals
  • Aortic Valve / cytology*
  • Aortic Valve / metabolism
  • Aortic Valve / pathology*
  • Aortic Valve Stenosis / metabolism*
  • Benzylamines / pharmacology
  • Calcinosis / metabolism*
  • Calcium Signaling
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Core Binding Factor Alpha 1 Subunit / drug effects
  • Core Binding Factor Alpha 1 Subunit / metabolism*
  • Cyclic AMP Response Element-Binding Protein / drug effects
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Inositol 1,4,5-Trisphosphate Receptors / antagonists & inhibitors
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Sulfonamides / pharmacology
  • Swine
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor A / pharmacology

Substances

  • Benzylamines
  • Core Binding Factor Alpha 1 Subunit
  • Cyclic AMP Response Element-Binding Protein
  • Inositol 1,4,5-Trisphosphate Receptors
  • Protein Kinase Inhibitors
  • Sulfonamides
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • KN 93
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2

Supplementary concepts

  • Aortic Valve, Calcification of