Calciprotein Particles Cause Endothelial Dysfunction under Flow

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.

Excessive Adventitial and Perivascular Vascularisation Correlates with Vascular Inflammation and Intimal Hyperplasia

“…To investigate the mechanism of the above-mentioned associations, we complemented the balloon angioplasty of rat abdominal aorta with daily intravenous injections of CPPs, a newly discovered trigger of endothelial dysfunction [ 42 , 43 , 44 ], for 5 days. Control rats were subjected to balloon injury alone.…”

The association of serum immunoglobulins with risk of cardiovascular disease and mortality: the Rotterdam Study

“…Vascular calci cation, including CAC, is strongly driven by in ammation (31,32). Calcifying nanoparticles are thought to play a causal role in vascular calci cation, potentially by promoting endothelial dysfunction and downregulation of atheroprotective transcription factors among others (33,34). Higher IgG levels directed against calcifying nanoparticles were demonstrated in Turkish individuals with CAC and these IgG levels correlated positively with CAC score (33).…”

Endothelial Dysfunction in the Context of Blood–Brain Barrier Modeling

“…Subsequent experiments showed that a 4-h incubation of primary coronary artery and internal thoracic artery endothelial cells with calciprotein particles causes adhesion of leukocytes to arterial endothelial cells under flow accompanied by an increase in VCAM1 and ICAM1 [ 82 – 84 ]. Both complete and vesicle-free conditioned medium from CPP-treated primary coronary artery endothelial cells led to an increased expression of VCAM1, ICAM1, SELE and SELP genes in combination with an elevated expression of IL6, CXCL8, CCL2, CXCL1 and MIF genes, increased expression of VCAM1 and ICAM1 receptors, and augmented release of IL-6, IL-8 and MCP-1/CCL2 when added to intact human coronary artery endothelial cells.…”