Calciprotein Particles Cause Endothelial Dysfunction under Flow

Int J Mol Sci. 2020 Nov 20;21(22):8802. doi: 10.3390/ijms21228802.

Abstract

Calciprotein particles (CPPs), which increasingly arise in the circulation during the disorders of mineral homeostasis, represent a double-edged sword protecting the human organism from extraskeletal calcification but potentially causing endothelial dysfunction. Existing models, however, failed to demonstrate the detrimental action of CPPs on endothelial cells (ECs) under flow. Here, we applied a flow culture system, where human arterial ECs were co-incubated with CPPs for 4 h, and a normolipidemic and normotensive rat model (10 daily intravenous injections of CPPs) to simulate the scenario occurring in vivo in the absence of confounding cardiovascular risk factors. Pathogenic effects of CPPs were investigated by RT-qPCR and Western blotting profiling of the endothelial lysate. CPPs were internalised within 1 h of circulation, inducing adhesion of peripheral blood mononuclear cells to ECs. Molecular profiling revealed that CPPs stimulated the expression of pro-inflammatory cell adhesion molecules VCAM1 and ICAM1 and upregulated transcription factors of endothelial-to-mesenchymal transition (Snail, Slug and Twist1). Furthermore, exposure to CPPs reduced the production of atheroprotective transcription factors KLF2 and KLF4 and led to YAP1 hypophosphorylation, potentially disturbing the mechanisms responsible for the proper endothelial mechanotransduction. Taken together, our results suggest the ability of CPPs to initiate endothelial dysfunction at physiological flow conditions.

Keywords: calciprotein particles; cell adhesion molecules; endothelial cells; endothelial dysfunction; endothelial-to-mesenchymal transition; laminar flow; mechanotransduction; monocyte adhesion; shear stress; turbulent flow.

MeSH terms

  • Animals
  • Calcifying Nanoparticles / adverse effects*
  • Calcium / chemistry
  • Cells, Cultured
  • Endothelial Cells / pathology*
  • Humans
  • Kruppel-Like Factor 4
  • Male
  • Mechanotransduction, Cellular*
  • Rats
  • Rats, Wistar
  • Stress, Mechanical
  • Vascular Diseases / metabolism

Substances

  • Calcifying Nanoparticles
  • KLF4 protein, human
  • Klf4 protein, rat
  • Kruppel-Like Factor 4
  • Calcium