Vascular Calcification: Comparison
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A variety of actively regulated processes on cellular and systemic level with various contributing and inhibiting factors can result in vascular calcification (VC). Currently, treatment is limited to management of risk factors including regulation of the calcium-phosphate metabolism. Due to the complex pathophysiology, the mechanisms underlying ectopic calcification are studied in various, distinctly different research models. Beside in vitro models using cells of different origin, ex vivo settings using aortic tissue are available. In addition, various in vivo disease-induced animal models are currently used in research. All of these experimental settings depict (patho)physiologic mechanisms within the vascular calcification process.

  • calcification
  • research models
  • in vitro
  • ex vivo
  • in vivo
  • mineralization

1. Introduction

The pathophysiology of VC is characterized by alterations of the vessel wall and dysregulation of mineralization inhibitors, ending in calcification of the media by mechanisms comparable to bone formation. Abnormal metabolic conditions such as uremia in the context of chronic kidney disease [1], impaired bone metabolism with hyperphosphatemia [2], hypercalcemia and diabetes mellitus type 2 [3][4] lead to medial located calcification and depict the idea of a systemic disease. This is further supported by a decrease in plasma concentrations of endogenous inhibitors of ectopic calcification like fetuin-a, matrix gla protein (MGP) and inorganic pyrophosphate (PPi) [5][6].

2. Vascular Calcification - Current Research Models

The vascular smooth muscle cell (VSMC) in the media of the vessel wall is one pivotal player in vascular calcification. A variety of conditions like inflammation [7], reactive oxygen species (ROS) [8][9] and senescence [10] induce a phenotype shift of the contractile VSMC to a synthetic state. Extracellular deposits such as matrix vesicles or apoptotic bodies from VSMC serve as a nucleation site for hydroxyapatite and therefore promote calcification [11][12][13]. Degradation of the extracellular matrix (ECM) by matrix metalloproteinases (MMP) facilitates hydroxyapatite deposition and osteoblastic trans-differentiation of VSMC [14]. Aside from that, other cell types are involved: mesenchymal osteoprogenitor cells, hematopoietic progenitor cells, endothelial progenitor cells and myeloid cells are circulating cells bearing osteogenic and calcifying potential [15].

This vast variety of influencing factors in the development of VC reflect, at least in part, the diversity of research models and vice versa. Therefore, studying vascular calcification entails the challenge of utilizing a manageable experimental setting reducing the complexity of its pathophysiologic interrelations while still representing a physiological setting.

The recent entreviewy [16] summarizes various cell types and experimental conditions for in vitro settings, currently available ex vivo protocols and different in vivo models using rats and mice with their limitations and advantages. The in vivo models are structured according to their background setting into naturally occurring and genetically modified models and depends on the induction of disease state into operation, substance application and special diet. In vitro models allow studying the signaling pathway under manageable conditions; however, provide the most non-physiological environment. Ex vivo settings using vessel tissue meet this drawback at least partly and might bridge the gap to in vivo models. While offering a natural environment, in vivo models require massive interventions to achieve the vascular calcification condition.

References

  1. Shanahan, C.M.; Crouthamel, M.H.; Kapustin, A.; Giachelli, C.M.; Arterial calcification in chronic kidney disease: key roles for calcium and phosphate. Circulation Research 2011, 109, 697-711.
  2. Lu, K.C.; Wu, C.C.; Yen, J.F.; Liu, W.C.; Vascular calcification and renal bone disorders. Scientific World Journal 2014, 2014, 637065.
  3. Lehto, S.; Niskanen, L.; Suhonen, M.; Ronnemaa, T.; Laakso; M.; Medial artery calcification. A neglected harbinger of cardiovascular complications in non-insulin-dependent diabetes mellitus.. Arteriosclerosis Thrombosis and Vascular Biology 1996, 16, 978-983.
  4. Niskanen, L.; Siitonen, O.; Suhonen, M.; Uusitupa, M.I.; Medial artery calcification predicts cardiovascular mortality in patients with NIDDM. Diabetes Care 1994, 17, 1252-1256.
  5. Moe, S.M.; Neal, C.X.; O´Neill, K.D., Brown, K.; Westenfeld, R.; Jahnen-Dechent, W.; Ketteler, M.; Fetuin-A and matrix gla protein (MGP) are important inhibitors of vascular calcification in CKD. Journal of American Society of Nephrology 2003, 14, 692A.
  6. Lomashvili, K.A.; Narisawa, S.; Millan, J.L.; O´Neill, W.C.; Vascular calcification is dependent on plasma levels of pyrophosphate. Kidney International 2014, 85, 1351-1356.
  7. Moe, S.M.; Chen, N.X.; Inflammation and vascular calcification. Blood Purification 2005, 23, 64-71.
  8. Mody, N.; Parhami, F.; Sarafian, T.A.; Demer, L.L.; Oxidative stress modulates osteoblastic differentiation of vascular and bone cells. Free Radical Biology and Medicine 2001, 31, 509-519.
  9. Byon, C.H.; Javed, A.; Dai, Q.; Kappes, J.C.; Clemens, T.L., Darley-Usmar, V.M.; McDonald, J.M.; Chen, Y.; Oxidative stress induces vascular calcification through modulation of the osteogenic transcription factor Runx2 by AKT signaling. Journal of Biology and Chemistry 2008, 283, 15319-15327.
  10. Sanchis, P.; Ho, C.Y.; Liu, Y.; Beltran, L.E.; Ahmad, S.; Jacob, A.P.; Furmanik, M.; Laycock, J.; Long, D.A., Shroff, R.; et al.; et al. Arterial "inflammating"drives vascular calcification in children on dialysis. Kidney International 2019, 95, 958-972.
  11. Proudfoot, D.; Stepper, J.N.; Hegyi, L.; Farzaneh-Far, A.; Shanahan, C.M.; Weissberg, P.L.; The role of apoptosis in the initiation of vascular calcification. Fur Kardiol 2001, 90 (Suppl. 3), 43-46.
  12. Proudfoot, D.; Skepper, J.N.; Hegyi, L.; Bennett, M.R.; Shanahan, C.M.; Weissberg, P.L.; Apoptosis regulates human vascular calcification in vitro: Evidence for initiation of vascular calcification by apoptotic bodies. Circulation Research 2000, 87, 1055-1062.
  13. New, S.E.; Aikawa, E.; Role of extracellular vesicles in de novo mineralization: An additional novel mechanism of cardiovascular calcification. Arteriosclerosis Thrombosis and Vascular Biology 2013, 33, 1753-1758.
  14. Lei,Y.; Sinha, A.; Nosoudi, N.; Grover, A.; Vyavahare, N.; Hydroxyapatite and calcified elastin induce osteoblast-like differentiation in rat aortic smooth muscle cells. Experimental Cell Research 2014, 323, 198-208.
  15. Albiero, M.; Avogadro, A.; Fadini, G.P.; Circulating cellular players in vascular calcification. Current Pharmaceutical Design 2014, 20, 5889-5896.
  16. Herrmann, J.; Babic, M.; Tölle, M.; van der Giet, M.; Schuchardt, M.; Research models for studying vascular calcification. International Journal of Molecular Science 2020, 21, 2204.
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