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Purinergic regulation of vascular endothelial growth factor signaling in angiogenesis

S M Rumjahn1, N Yokdang, K A Baldwin

  • 1Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.

British Journal of Cancer
|April 16, 2009
PubMed

Insights

P2Y1 receptors activate vascular endothelial growth factor receptor-2 (VEGFR-2) to promote angiogenesis. This interaction is crucial for blood vessel formation in vascular homeostasis and tumor growth.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • P2Y purine nucleotide receptors (P2YRs) are involved in endothelial cell tubulogenesis.
  • Breast cancer cells secrete nucleoside diphosphate kinase (NDPK), influencing angiogenesis.
  • The role of P2Y1 receptors in transactivating VEGFR-2 in angiogenic signaling requires further investigation.

Purpose of the Study:

  • To test the hypothesis that activated P2Y1 receptors transactivate VEGFR-2 in angiogenic signaling.
  • To investigate the interaction between P2Y1R and VEGFR-2 in endothelial cell tubulogenesis.
  • To elucidate the signaling pathway involving P2Y1R and VEGFR-2 in angiogenesis.

Main Methods:

  • Stimulation of P2Y1R with 2-methyl-thio-ATP (2MS-ATP) and assessment of angiogenesis.
  • Inhibition of VEGFR-2 tyrosine kinase activity using SU1498.
  • Measurement of VEGFR-2 phosphorylation at tyr1175 following stimulation with 2MS-ATP and VEGF.
  • Dose-dependent analysis of 2MS-ATP on endothelial cell (EC) tubulogenesis.
  • Assessment of additive and saturated effects of combined 2MS-ATP and VEGF stimulation.

Main Results:

  • P2Y1R stimulation of angiogenesis was suppressed by a VEGFR-2 inhibitor.
  • VEGF and 2MS-ATP induced comparable phosphorylation of VEGFR-2 at tyr1175.
  • 2MS-ATP dose-dependently stimulated EC tubulogenesis.
  • Additive effects of 2MS-ATP and sub-maximal VEGF were observed at lower 2MS-ATP concentrations, with saturated and less than additive effects at higher concentrations.

Conclusions:

  • VEGF receptor can be activated independently of VEGF.
  • The P2Y1R-VEGFR2 interaction is critical for vascular homeostasis.
  • This signaling pathway plays a key role in tumor-mediated angiogenesis.

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