Adenosine receptor activation induces vascular endothelial growth factor in human retinal endothelial cells

Maria B. Grant, Roy W. Tarnuzzer, Sergio Caballero, Mark J. Ozeck, Margaret I. Davis, Polyxenie E. Spoerri, Igor Feoktistov, Italo Biaggioni, John C. Shryock, Luiz Belardinelli

Research output: Contribution to journalArticle

144 Citations (Scopus)

Abstract

Adenosine, released in increased amounts by hypoxic tissues, is thought to be an angiogenic factor that links altered cellular metabolism caused by oxygen deprivation to compensatory angiogenesis. Adenosine interacts with 4 subtypes of G protein-coupled receptors, termed A1, A(2A), A(2B), and A3. We investigated whether adenosine causes proliferation of human retinal endothelial cells (HRECs) and synthesis of vascular endothelial growth factor (VEGF) and, if so, which adenosine receptor subtype mediates these effects. The nonselective adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA), in a concentration-dependent manner, increased both VEGF mRNA and protein expression by HRECs, as well as proliferation. This proliferative effect of NECA was inhibited by the addition of anti-human VEGF antibody. NECA also increased insulin-like growth factor-I and basic fibroblast growth factor mRNA expression in a time-dependent manner and cAMP accumulation in these cells. In contrast, neither the A1 agonist N6-cyclopentyladenosine nor the A(2A) agonist 2-p-(2-carboxyethyl) phenethylamino-NECA caused any of the above effects of NECA. The effects of NECA were not significantly attenuated by either the A(2A) antagonist SCH58261 or the A1 antagonist 8- cyclopentyl-1,3-dipropylxanthine. However, the nonselective adenosine receptor antagonist xanthine amine congener completely inhibited the effects of NECA. Addition of antisense oligonucleotide complementary to A(2B) adenosine receptor mRNA inhibited VEGF protein production by HRECs after NECA stimulation. Thus, the A(2B) adenosine receptor subtype appears to mediate the actions of adenosine to increase growth factor production, cAMP content, and cell proliferation of HRECs. Adenosine activates the A(2B) adenosine receptor in HRECs, which may lead to neovascularization by a mechanism involving increased angiogenic growth factor expression.

Original languageEnglish (US)
Pages (from-to)699-706
Number of pages8
JournalCirculation Research
Volume85
Issue number8
StatePublished - Oct 15 1999
Externally publishedYes

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Adenosine-5'-(N-ethylcarboxamide)
Purinergic P1 Receptors
Endothelial Cells
Adenosine A2B Receptors
Adenosine
Vascular Endothelial Growth Factor A
Angiogenesis Inducing Agents
Messenger RNA
Intercellular Signaling Peptides and Proteins
Purinergic P1 Receptor Agonists
Purinergic P1 Receptor Antagonists
Xanthine
human VEGFA protein
Antisense Oligonucleotides
Fibroblast Growth Factor 2
Insulin-Like Growth Factor I
Amines
Proteins
Cell Proliferation
Oxygen

Keywords

  • Adenosine receptor
  • Angiogenesis
  • Diabetes
  • Hypoxia
  • Ischemia

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Grant, M. B., Tarnuzzer, R. W., Caballero, S., Ozeck, M. J., Davis, M. I., Spoerri, P. E., ... Belardinelli, L. (1999). Adenosine receptor activation induces vascular endothelial growth factor in human retinal endothelial cells. Circulation Research, 85(8), 699-706.

Adenosine receptor activation induces vascular endothelial growth factor in human retinal endothelial cells. / Grant, Maria B.; Tarnuzzer, Roy W.; Caballero, Sergio; Ozeck, Mark J.; Davis, Margaret I.; Spoerri, Polyxenie E.; Feoktistov, Igor; Biaggioni, Italo; Shryock, John C.; Belardinelli, Luiz.

In: Circulation Research, Vol. 85, No. 8, 15.10.1999, p. 699-706.

Research output: Contribution to journalArticle

Grant, MB, Tarnuzzer, RW, Caballero, S, Ozeck, MJ, Davis, MI, Spoerri, PE, Feoktistov, I, Biaggioni, I, Shryock, JC & Belardinelli, L 1999, 'Adenosine receptor activation induces vascular endothelial growth factor in human retinal endothelial cells', Circulation Research, vol. 85, no. 8, pp. 699-706.
Grant MB, Tarnuzzer RW, Caballero S, Ozeck MJ, Davis MI, Spoerri PE et al. Adenosine receptor activation induces vascular endothelial growth factor in human retinal endothelial cells. Circulation Research. 1999 Oct 15;85(8):699-706.
Grant, Maria B. ; Tarnuzzer, Roy W. ; Caballero, Sergio ; Ozeck, Mark J. ; Davis, Margaret I. ; Spoerri, Polyxenie E. ; Feoktistov, Igor ; Biaggioni, Italo ; Shryock, John C. ; Belardinelli, Luiz. / Adenosine receptor activation induces vascular endothelial growth factor in human retinal endothelial cells. In: Circulation Research. 1999 ; Vol. 85, No. 8. pp. 699-706.
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