Purinergic regulation of vascular endothelial growth factor signaling in angiogenesis.
P2Y purine nucleotide receptors (P2YRs) promote endothelial cell tubulogenesis through breast cancer cell-secreted nucleoside diphosphate kinase (NDPK). We tested the hypothesis that activated P2Y(1) receptors transactivate vascular endothelial growth factor receptor (VEGFR-2) in angiogenic signaling. P2Y(1)R stimulation (10 microM 2-methyl-thio-ATP (2MS-ATP)) of angiogenesis is suppressed by the VEGFR-2 tyrosine kinase inhibitor, SU1498 (1 microM). Phosphorylation of VEGFR-2 by 0.0262 or 2.62 nM VEGF was comparable with 0.01 or 10 microM 2MS-ATP stimulation of the P2Y(1)R. 2MS-ATP, and VEGF stimulation increased tyrosine phosphorylation at tyr1175. 2MS-ATP (0.1-10 microM) also stimulated EC tubulogenesis in a dose-dependent manner. The addition of sub-maximal VEGF (70 pM) in the presence of increasing concentrations of 2MS-ATP yielded additive effects at 2MS-ATP concentrations <3 microM, whereas producing saturated and less than additive effects at > or =3 microM. We propose that the VEGF receptor can be activated in the absence of VEGF, and that the P2YR-VEGFR2 interaction and resulting signal transduction is a critical determinant of vascular homoeostasis and tumour-mediated angiogenesis.
Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
S M
SM
Rumjahn
N
N
Yokdang
K A
KA
Baldwin
J
J
Thai
I L O
IL
Buxton
D001943:Breast Neoplasms / Q000098:blood supply / Q000473:pathology; D002320:Cardiovascular Physiological Phenomena; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000503:physiopathology*; D010766:Phosphorylation; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058472:Receptors, Purinergic P2Y1; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology
C546382:P2RY1 protein, human; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2