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.
The recently discovered dinucleotide uridine adenosine tetraphosphate (Up(4)A) was found in human plasma and characterized as endothelium-derived vasoconstrictive factor (EDCF). A further study revealed a positive correlation between Up(4)A 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 Up(4)A. Indeed, we found a strong chemoattractant effect of Up(4)A 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, Up(4)A mediates it's migratory signal mainly via the P2Y(2). 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 Up(4)A stimulation in the PDGFR-β knockdown cells compared to control cells. In this study, we present substantiate data that Up(4)A 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 P2Y(2) by Up(4)A and via transactivation of the PDGFR.
Charité - Universitätsmedizin Berlin, CharitéCentrum, Department of Nephrology, Campus Benjamin Franklin, Germany.
Annette
A
Wiedon
Markus
M
Tölle
Joschika
J
Bastine
Mirjam
M
Schuchardt
Tao
T
Huang
Vera
V
Jankowski
Joachim
J
Jankowski
Walter
W
Zidek
Markus
M
van der Giet
D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D015226:Dinucleoside Phosphates / Q000494:pharmacology / Q000502:physiology*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058473:Receptors, Purinergic P2Y2 / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology
D015226:Dinucleoside Phosphates; D034741:RNA, Small Interfering; D058473:Receptors, Purinergic P2Y2; D020032:Tyrphostins; C529314:uridine adenosine tetraphosphate; C106250:6,7-dimethoxy-3-phenylquinoxaline; D020796:Receptor, Platelet-Derived Growth Factor alpha; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1