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Background <p>Vascular calcification is highly prevalent in Chronic Kidney Disease (CKD) and is associated with markedly increased cardiovascular risk. High serum phosphate in CKD increases calcification propensity via generation of circulating calciprotein particles (CPP2), crystalline nanoaggregates composed of calcium, phosphate, and serum proteins. CPP2 induce vascular calcification in vascular smooth muscle cells (VSMCs) in vitro. In vivo, endothelial cells, rather than VSMCs are primarily exposed to CPP2, yet understanding the influence of endothelial cells on vascular calcification is limited.</p> Methods <p>We investigated calcification-promoting signalling by endothelial cells on VSMCs. Effects of CPP2 exposure to endothelial cells on CPP2 uptake, endothelial cell activation, and endothelial cell-derived secretome were studied. Effects of the secretome on VSMC calcification were investigated. Using NanoString nCounter analysis the effects of CPP2-activated endothelial cell-conditioned medium on VSMCs gene expression were mapped.</p> Results <p>Endothelial cells internalise CPP2 and elevate ICAM-1, E-selectin, and VCAM-1-mRNA expression, indicating endothelial activation. VSMCs cultured in conditioned medium from CPP2-activated endothelial cells demonstrated enhanced calcification, suggesting that CPP2-activated endothelial cells release pro-calcifying soluble factors. Mass spectrometry was utilized to identify 1171 proteins in the CPP2-activated endothelial cells’ secretome. Among these, 76 proteins were differentially expressed compared to control endothelial cells’ secretome, including proteins related to blood vessel development, extracellular matrix remodelling, and oxidative stress-related processes. Finally, endothelial cell-derived paracrine factors present in conditioned medium enhanced mRNA-expression of calcification-related factors in VSMCs.</p> Conclusions <p>CPP2-activated endothelial cells promote VSMC calcification via paracrine signalling. In response to these paracrine factors, VSMCs increase the expression of pro-calcification genes.</p>

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Calciprotein particle-activated endothelial cells aggravate smooth muscle cell calcification via paracrine signalling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月26日

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  • Lian Feenstra,
  • Lara W. Zeper,
  • Brenda van de Langenberg,
  • Eveline J. E. M. Kahlman,
  • Guido de La Roij,
  • Melanie Reijrink,
  • Benoit Bernay,
  • Laurent Chatre,
  • Jeroen Kuipers,
  • Ben N. G. Giepmans,
  • Mirjam F. Mastik,
  • Wierd Kooistra,
  • Monique E. Lodewijk,
  • Malou Zuidscherwoude,
  • Robert A. Pol,
  • Coby Annema,
  • Stephan J. L. Bakker,
  • Stefan P. Berger,
  • Hans Blokzijl,
  • Frank A. J. A. Bodewes,
  • Marieke T. de Boer,
  • Kevin Damman,
  • Martin H. de Borst,
  • Arjan Diepstra,
  • Gerard Dijkstra,
  • Rianne M. Douwes,
  • Caecilia S. E. Doorenbos,
  • Michele F. Eisenga,
  • Michiel E. Erasmus,
  • C. Tji Gan,
  • Antonio W. Gomes Neto,
  • Eelko Hak,
  • Bouke G. Hepkema,
  • Marius C. van den Heuvel,
  • Frank Klont,
  • Tim J. Knobbe,
  • Daan Kremer,
  • Coretta van Leer-Buter,
  • Henri G. D. Leuvenink,
  • Marco van Londen,
  • Willem S. Lexmond,
  • Vincent E. de Meijer,
  • Hubert G. M. Niesters,
  • Gertrude J. Nieuwenhuis-Moeke,
  • L. Joost van Pelt,
  • Robert J. Porte,
  • Adelita V. Ranchor,
  • Jan Stephan F. Sanders,
  • Marion J. Siebelink,
  • Riemer J. H. J. A. Slart,
  • J. Cas Swarte,
  • Daan J. Touw,
  • Charlotte A. te Velde-Keyzer,
  • Erik A. M. Verschuuren,
  • Michel J. Vos,
  • Rinse K. Weersma,
  • Edward. R. Smith,
  • Guido Krenning,
  • Jeroen H. F. de Baaij,
  • Jan-Luuk Hillebrands,
  • Joost G. J. Hoenderop

摘要

Background

Vascular calcification is highly prevalent in Chronic Kidney Disease (CKD) and is associated with markedly increased cardiovascular risk. High serum phosphate in CKD increases calcification propensity via generation of circulating calciprotein particles (CPP2), crystalline nanoaggregates composed of calcium, phosphate, and serum proteins. CPP2 induce vascular calcification in vascular smooth muscle cells (VSMCs) in vitro. In vivo, endothelial cells, rather than VSMCs are primarily exposed to CPP2, yet understanding the influence of endothelial cells on vascular calcification is limited.

Methods

We investigated calcification-promoting signalling by endothelial cells on VSMCs. Effects of CPP2 exposure to endothelial cells on CPP2 uptake, endothelial cell activation, and endothelial cell-derived secretome were studied. Effects of the secretome on VSMC calcification were investigated. Using NanoString nCounter analysis the effects of CPP2-activated endothelial cell-conditioned medium on VSMCs gene expression were mapped.

Results

Endothelial cells internalise CPP2 and elevate ICAM-1, E-selectin, and VCAM-1-mRNA expression, indicating endothelial activation. VSMCs cultured in conditioned medium from CPP2-activated endothelial cells demonstrated enhanced calcification, suggesting that CPP2-activated endothelial cells release pro-calcifying soluble factors. Mass spectrometry was utilized to identify 1171 proteins in the CPP2-activated endothelial cells’ secretome. Among these, 76 proteins were differentially expressed compared to control endothelial cells’ secretome, including proteins related to blood vessel development, extracellular matrix remodelling, and oxidative stress-related processes. Finally, endothelial cell-derived paracrine factors present in conditioned medium enhanced mRNA-expression of calcification-related factors in VSMCs.

Conclusions

CPP2-activated endothelial cells promote VSMC calcification via paracrine signalling. In response to these paracrine factors, VSMCs increase the expression of pro-calcification genes.