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Pericytes are multipotent mesenchymal stromal cells playing an active role in angiogenesis, vessel stabilisation, maturation, remodelling, blood flow regulation and are able to trans-differentiate into other cells of the mesenchymal lineage. In this review, we summarised recent data demonstrating that pericytes play a key role in the pathogenesis and development of atherosclerosis (AS). Pericytes are involved in lipid accumulation, inflammation, growth, and vascularization of the atherosclerotic plaque. Decreased pericyte coverage, endothelial and pericyte dysfunction is associated with intraplaque angiogenesis and haemorrhage, calcification and cholesterol clefts deposition. At the same time, pericytes can be used as a novel therapeutic target to promote vessel maturity and stability, thus reducing plaque vulnerability. Finally, we discuss recent studies exploring effective AS treatments with pericyte-mediated anti-atherosclerotic, anti-inflammatory and anti-apoptotic effects.

The present study was undertaken in order to extend of our earlier work, focusing on the analysis of roles of cell-to-cell communications in the regulation of the subendothelial cell function. In present study, we have found that the expression of connexin43 (Cx43) is dramatically reduced in human atherosclerotic lesions, compared with undiseased intima. In atherosclerotic lesions, the number of so-called 'connexin plaques' was found to be lower in lipid-laden cells than in cells which were free from lipid inclusions. In primary cell culture, subendothelial intimal cells tended to create multicellular structures in the form of clusters. Cluster creation was accompanied by the formation of gap junctions between cells; the degree of gap junctional communication correlated with the density of cells in culture. We found that atherosclerosis-related processes such as DNA synthesis, protein synthesis and accumulation of intracellular cholesterol correlated with the degree of cell-to-cell communication. The relation of DNA and protein synthesis with cell-to-cell communication could be described as "bell-shaped". We further incubated cells, cultured from undiseased subendothelial intima, with various forms of modified LDL causing intracellular cholesterol accumulation. After the incubation of intimal cells with modified LDL, intercellular communication has "dropped" considerably. The findings indicate that intracellular lipid accumulation might be a reason for a decrease of the number of gap junctions. The findings also suggest that the disintegration of cellular network is associated with foam cell formation, the process known as a key event of atherogenesis., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In previous studies, we showed that ganglioside levels (GM3 being the main ganglioside) in human aortic intima isolated from atherosclerotic lesions were 5 times greater compared to intima from non-diseased vascular areas. Recently, we found that GM3 and GM3 synthase levels in differentiated in vitro macrophages were five and ten times higher, respectively, compared to freshly isolated human monocytes. In this article, we report that GM3 synthase mRNA levels were significantly higher in differentiated human monocyte-derived macrophages compared to monocytes and in atherosclerotic aorta compared to normal aorta. The depletion of GM3 synthesis in cultured monocyte-derived macrophages with DL-threo-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol, an inhibitor of ganglioside synthesis, delayed the acquisition of CD206 antigen, prevented the loss of CD163 antigen and enhanced anti-inflammatory cytokine (CCL18) secretion. In the current study, we performed purification of CMP-N-acetylneuraminic acid:lactosylceramide alpha2,3-sialyltransferase (GM3 synthase) from Triton X-100 extract of human blood mononuclear cells by immunoaffinity chromatography on Sepharose coupled with anti-GM3 synthase antibody. Comparison with several glycolipid substrates showed high specificity of the purified enzyme for lactosylceramide. The apparent K(M) for lactosylceramide and CMP-NeuAc were 101 and 180 muM, respectively. Analysis of the purified enzyme by SDS-PAGE followed by the anti-GM3 synthase antibody probing detected two bands with apparent molecular masses of 60 and 64 kDa. There were no other protein bands as revealed by Coomassie Blue staining. Thus, ganglioside GM3 may be considered as a physiological modulator of macrophage differentiation in human atherosclerotic aorta. The presented data suggest that up-regulation of GM3 levels is an element of monocyte/macrophage differentiation that provides a tool for control of macrophage accumulation in inflammatory loci.

Abstract: Inflammatory reactions driven by an accumulation in the intima of immune-inflammatory cells and focal lipid depositions are the hallmarks of atherogenesis. It is commonly accepted that immune-inflammatory cell accumulation and lipid deposition are associated with the very earlier stage of atherosclerosis but no study has yet focused on the determination of quantitative values of this association. The present study examined correlations between lipid deposition, immune-inflammatory cell content and major histocompatibility complex (MHC) class II molecule HLA-DR expression in diffuse intimal thickening (DIT), which is thought to represent the earliest macroscopic manifestation of atherosclerosis. In parallel consecutive tissue sections of DIT, lipids were examined by chromatographic analysis (including triglycerides, cholesteryl esters, free cholesterol and phospholipids), histochemically, using Oil Red O staining, and by electron microscopy. Immune-inflammatory cells and HLA-DR expression were examined immunohistochemically in consecutive sections of the same tissue specimens. The study revealed that lipids exhibited a non-uniform distribution throughout the intima. In the juxtaluminal sublayer, lipids were localized both intracellularly and extracellularly, whereas in the juxtamedial musculoelastic sublayer, lipids were present predominantly along elastic fibers. Lipid deposits were found to positively correlate with HLA-DR expression (r =0.79; p <0.001). The study also identified a positive correlation between lipid deposition and immune-inflammatory cell content but the correlation values varied between different sublayers of the tunica intima. The correlation between lipid deposition and immune-inflammatory cell content in the juxtaluminal sublayer of the intima was notably stronger (r =0.69; p <0.001) than in the juxtamedial musculoelastic layer (r =0.28; p <0.001). The findings of the present study support a view that lipid accumulation in the intima plays a role in the initiation of inflammatory reaction and that at the pre-lesional stage in the development of atherosclerosis, lipid-associated immune cell activation might occur primarily in the juxtaluminal portion of the intima. [Copyright &y& Elsevier]

Pericytes are mural vascular cells covering microvascular capillaries, where they contribute to the formation, maturation, maintenance, stabilisation and remodelling of vasculature. They actively interact and communicate with other cells to maintain the capillary structural integrity, vascular permeability and blood flow. Pericytes are crucial participants in the physiological and pathological processes of cardiovascular disease. In this review, we summarise recent data regarding pericyte metabolism, trans-differentiation, angiogenesis and immunomodulation in connection with different cardiovascular pathologies. Further, we discuss an application of pericytes as a new cell therapy approach to treat coronary artery disease, congenital heart disease, atherosclerotic plaques calcification and calcific valvular heart disease in different in vivo animal models and in vitro studies. Also, we discuss different methods and pharmacological therapies for CVDs treatment with pericyte-mediated effects. Finally, we present a comprehensive overview of the role of pericytes in CVDs and as a pharmacological target for different novel drugs and techniques and highlight the potential application of pericytes to treat CVDs. • Pericytes constriction reduces microvascular blood flow after ischaemia (no-reflow). • Pericytes constriction may be regulated with IPC technique and pharmacologically. • Pericytes transplantation ameliorates tissue remodelling after myocardial infarction. • Pericytes cellularize prosthetic materials, thus improving grafts and valve integration. [ABSTRACT FROM AUTHOR]