Cross-talk between macrophages and smooth muscle cells impairs collagen and metalloprotease synthesis and promotes angiogenesis

• Published in: Biochimica et biophysica acta Vol. 1863; no. 7; pp. 1568 - 1578
• Main Authors: Butoi, E., Gan, A.M., Tucureanu, M.M., Stan, D., Macarie, R.D., Constantinescu, C., Calin, M., Simionescu, M., Manduteanu, I.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-07-2016
• Subjects: Angiogenesis; Atherosclerosis; Atherosclerosis - enzymology; Atherosclerosis - genetics; Atherosclerosis - pathology; Atherosclerosis - physiopathology; Cell Communication; Cell Line; Coculture Techniques; Collagen - metabolism; Culture Media, Conditioned - metabolism; Extracellular matrix proteins; Humans; Inflammation Mediators - metabolism; Interleukin-1beta - metabolism; Macrophages - enzymology; Macrophages - pathology; Macrophage–SMC cross-talk; Matrix Metalloproteinase 1 - metabolism; Matrix Metalloproteinase 9 - metabolism; Matrix metalloproteinases; Muscle, Smooth, Vascular - enzymology; Muscle, Smooth, Vascular - pathology; Muscle, Smooth, Vascular - physiopathology; Myocytes, Smooth Muscle - enzymology; Myocytes, Smooth Muscle - pathology; Neovascularization, Physiologic; RNA Interference; Signal Transduction; Time Factors; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - metabolism; Transfection; Vascular Endothelial Growth Factor A - metabolism; Angiogenesis; Macrophage–SMC cross-talk; Matrix metalloproteinases; Extracellular matrix proteins; Atherosclerosis
• ISSN: 0167-4889; 0006-3002; 1879-2596
• DOI: 10.1016/j.bbamcr.2016.04.001

Coronary atherosclerosis complicated by plaque disruption and thrombosis is a critical event in myocardial infarction and stroke, the major causes of cardiovascular death. In atherogenesis, macrophages (MAC) and smooth muscle cells (SMC) are key actors; they synthesize matrix components and numerous factors involved in the process. Here, we design experiments to investigate whether SMC–MAC communication induces changes in ECM protein composition and/or neo-angiogenesis. Cell to cell communication was achieved using trans-well chambers, where SMCs were grown in the upper chamber and differentiated MAC in the bottom chamber for 24 or 72h. We found that cross-talk between MAC and SMC during co-culture: (i) significantly decreased the expression of ECM proteins (collagen I, III, elastin) in SMC; (ii) increased the expression and activity of metalloprotease MMP-9 and expression of collagenase MMP-1, in both MAC and SMC; (iii) augmented the secretion of soluble VEGF in the conditioned media of cell co-culture and VEGF gene expression in both cell types, compared with control cells. Moreover, the conditioned media collected from MAC–SMC co-culture promoted endothelial cell tube formation in Matrigel, signifying an increased angiogenic effect. In addition, the MAC–SMC communication led to an increase in inflammatory IL-1β and TLR-2, which could be responsible for cellular signaling. In conclusion, MAC–SMC communication affects factors and molecules that could alter ECM composition and neo-angiogenesis, features that could directly dictate the progression of atheroma towards the vulnerable plaque. Targeting the MAC–SMC cross-talk may represent a novel therapeutic strategy to slow-down or retard the plaque progression.
•MAC and SMC cross-talk decreases the expression of extracellular matrix proteins.•MMP-1 and MMP-9 are increased by cell-to-cell cross-talk.•Soluble factors released by cell-to-cell cross-talk have angiogenic properties.•IL-1β and TLR-2 mediate endothelial tube-like formation.