title: Uridine adenosine tetraphosphate activation of the purinergic receptor P2Y enhances in vitro vascular calcification.
abstract: Purinergic signaling has a crucial role in different vascular processes. The endothelial-derived vasoconstrictor uridine adenosine tetraphosphate (Up(4)A) is a potent activator of the purinoceptor P2Y and is released under pathological conditions. Here we sought to measure purinergic effects on vascular calcification and initially found that Up(4)A plasma concentrations are increased in patients with chronic kidney disease. Exploring this further we found that exogenous Up(4)A enhanced mineral deposition under calcifying conditions ex vivo in rat and mouse aortic rings and in vitro in rat vascular smooth muscle cells. The addition of Up(4)A increased the expression of different genes specific for osteochondrogenic vascular smooth muscle cells such as Cbfa1, while decreasing the expression of SM22α, a marker specific for vascular smooth muscle cells. The influence of different P2Y antagonists on Up(4)A-mediated process indicated that P2Y(2/6) receptors may be involved. Mechanisms downstream of P2Y signaling involved phosphorylation of the mitogen-activated kinases MEK and ERK1/2. Thus, Up(4)A activation of P2Y influences phenotypic transdifferentiation of vascular smooth muscle cells to osteochondrogenic cells, suggesting that purinergic signaling may be involved in vascular calcification.
authors.affiliation: Department of Nephrology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Schuchardt
authors.forename: Markus
authors.initials: M
authors.lastname: Tölle
authors.forename: Jasmin
authors.initials: J
authors.lastname: Prüfer
authors.forename: Nicole
authors.initials: N
authors.lastname: Prüfer
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.forename: Vera
authors.initials: V
authors.lastname: Jankowski
authors.forename: Joachim
authors.initials: J
authors.lastname: Jankowski
authors.forename: Walter
authors.initials: W
authors.lastname: Zidek
authors.forename: Markus
authors.initials: M
authors.lastname: van der Giet
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000502:physiology; D015226:Dinucleoside Phosphates / Q000097:blood / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D015675:Osteocalcin / Q000502:physiology; D053495:Osteopontin / Q000502:physiology; D051381:Rats; D011921:Rats, Inbred WKY; D058470:Receptors, Purinergic P2Y / Q000502:physiology*; D015398:Signal Transduction; D061205:Vascular Calcification / Q000209:etiology*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D015226:Dinucleoside Phosphates; D058470:Receptors, Purinergic P2Y; C529314:uridine adenosine tetraphosphate; D015675:Osteocalcin; D053495:Osteopontin