Uridine adenosine tetraphosphate (Up4A) is a strong inductor of smooth muscle cell migration via activation of the P2Y2 receptor and cross-communication to the PDGF receptor

• Published in: Biochemical and biophysical research communications 2012-01, Vol.417 (3), p.1035-1040
• Main Authors: Wiedon, Annette, Tölle, Markus, Bastine, Joschika, Schuchardt, Mirjam, Huang, Tao, Jankowski, Vera, Jankowski, Joachim, Zidek, Walter, van der Giet, Markus
• Format: Article
• Language: English
• Subjects: Animals; Atherosclerosis; Cell Movement; Cells, Cultured; Dinucleoside Phosphates - pharmacology; Dinucleoside Phosphates - physiology; Dinucleotide; MAP Kinase Kinase 1 - metabolism; Migration; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - physiology; Osteopontin; P2Y; PDGF receptor transactivation; Purinoceptors; Rats; Receptor, Platelet-Derived Growth Factor alpha - antagonists & inhibitors; Receptor, Platelet-Derived Growth Factor alpha - genetics; Receptor, Platelet-Derived Growth Factor alpha - metabolism; Receptors, Purinergic P2Y2 - metabolism; RNA, Small Interfering - genetics; Tyrphostins - pharmacology; Up4A; Vascular smooth muscle cells
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2011.12.088

► Up4A induces VSMC migration. ► VSMC migration towards Up4A involves P2Y2 activation. ► Up4A-induced VSMC migration is OPN-dependent. ► Activation of ERK1/2 pathway is necessary for VSMC migration towards Up4A. ► Up4A-directed VSMC migration cross-communicates with the PDGFR. The recently discovered dinucleotide uridine adenosine tetraphosphate (Up4A) was found in human plasma and characterized as endothelium-derived vasoconstrictive factor (EDCF). A further study revealed a positive correlation between Up4A and vascular smooth muscle cell (VSMC) proliferation. Due to the dominant role of migration in the formation of atherosclerotic lesions our aim was to investigate the migration stimulating potential of Up4A. Indeed, we found a strong chemoattractant effect of Up4A on VSMC by using a modified Boyden chamber. This migration dramatically depends on osteopontin secretion (OPN) revealed by the reduction of the migration signal down to 23% during simultaneous incubation with an OPN-blocking antibody. Due to inhibitory patterns using specific and unspecific purinoreceptor inhibitors, Up4A mediates it’s migratory signal mainly via the P2Y2. The signaling behind the receptor was investigated with luminex technique and revealed an activation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathway. By use of the specific PDGF receptor (PDGFR) inhibitor AG1296 and siRNA technique against PDGFR-β we found a strongly reduced migration signal after Up4A stimulation in the PDGFR-β knockdown cells compared to control cells. In this study, we present substantiate data that Up4A exhibits migration stimulating potential probably involving the signaling cascade of MEK1 and ERK1/2 as well as the matrix protein OPN. We further suggest that the initiation of the migration process occurs predominant through direct activation of the P2Y2 by Up4A and via transactivation of the PDGFR.