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Mast Cell–Mediated Stimulation of Angiogenesis

Cooperative Interaction Between A_2B and A₃ Adenosine Receptors

From the Divisions of Cardiovascular Medicine (I.F., A.E.G.) and Clinical Pharmacology (S.R., I.B.), Departments of Medicine (I.F., S.R., A.E.G., I.B.) and Pharmacology (I.F., I.B.), Vanderbilt University, Nashville, Tenn.

Correspondence to Igor Feoktistov, PhD, 360 PRB, Vanderbilt University, Nashville, TN 37232-6300. E-mail igor.feoktistov{at}mcmail.vanderbilt.edu

Adenosine is released during tissue injury, ischemia and tumor growth, and promotes angiogenesis. Because mast cells accumulate in the proximity of new blood vessel development, we examined if they may contribute to adenosine-induced angiogenesis. We found that HMC-1 human mast cells express A_2A, A_2B, and A₃ adenosine receptors. The adenosine agonist NECA (100 µmol/L) increased interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), and angiopoietin-2 mRNA expression. NECA-induced secretion of IL-8 and VEGF was verified by ELISA. A_2B receptors mediate VEGF and IL-8 secretion because neither CGS21680 (selective A_2A agonist) nor IB-MECA (selective A₃ agonist) produced this effect, and it was inhibited by the selective A_2B antagonist IPDX but not by the selective A_2A antagonist SCH58261 or the selective A₃ antagonist MRS1191. In contrast, the selective A₃ agonist IB-MECA (EC₅₀ 1 nmol/L) stimulated angiopoietin-2 expression. Conditioned media from NECA-activated HMC-1 stimulated human umbilical vein endothelial cell proliferation and migration, and induced capillary tube formation. Capillary formation induced by mast cell–conditioned media was maximal if both HMC-1 A_2B and A₃ receptors were activated, whereas activation of A_2B receptor alone was less effective. Thus, adenosine A_2B and A₃ receptors act in a functional cooperative fashion to promote angiogenesis by a paracrine mechanism involving the differential expression and secretion of angiogenic factors from human mast cells.

Key Words: adenosine receptors • mast cells • angiogenesis • angiopoietin-2 • vascular endothelial growth factor

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