This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 92/5/485    most recent 01.RES.0000061572.10929.2Dv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Feoktistov, I. Articles by Biaggioni, I. Search for Related Content PubMed PubMed Citation Articles by Feoktistov, I. Articles by Biaggioni, I. Related Collections Angiogenesis Cell signalling/signal transduction Growth factors/cytokines

(Circulation Research. 2003;92:485.)
© 2003 American Heart Association, Inc.

Molecular Medicine

Mast Cell–Mediated Stimulation of Angiogenesis

Cooperative Interaction Between A_2B and A₃ Adenosine Receptors

Igor Feoktistov, Sergey Ryzhov, Anna E. Goldstein, Italo Biaggioni

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

This article has been cited by other articles:

				Y.-H. Kim, H.-S. Hwang, Y.-T. Kim, H.-S. Kim, and Y.-W. Park Modulation of Matrix Metalloproteinase Secretion by Adenosine A3 Receptor in Preeclamptic Villous Explants Reproductive Sciences, November 1, 2008; 15(9): 939 - 949. [Abstract] [PDF]

				S. Ryzhov, R. Zaynagetdinov, A. E. Goldstein, S. V. Novitskiy, M. M. Dikov, M. R. Blackburn, I. Biaggioni, and I. Feoktistov Effect of A2B Adenosine Receptor Gene Ablation on Proinflammatory Adenosine Signaling in Mast Cells J. Immunol., June 1, 2008; 180(11): 7212 - 7220. [Abstract] [Full Text] [PDF]

				S. Ryzhov, N. V. Solenkova, A. E. Goldstein, M. Lamparter, T. Fleenor, P. P. Young, J. P. Greelish, J. G. Byrne, D. E. Vaughan, I. Biaggioni, et al. Adenosine Receptor-Mediated Adhesion of Endothelial Progenitors to Cardiac Microvascular Endothelial Cells Circ. Res., February 15, 2008; 102(3): 356 - 363. [Abstract] [Full Text] [PDF]

				H. R. Ansari, A. Nadeem, S. L. Tilley, and S. J. Mustafa Involvement of COX-1 in A3 adenosine receptor-mediated contraction through endothelium in mice aorta Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3448 - H3455. [Abstract] [Full Text] [PDF]

				J. A. Auchampach Adenosine Receptors and Angiogenesis Circ. Res., November 26, 2007; 101(11): 1075 - 1077. [Full Text] [PDF]

				A. N. Clark, R. Youkey, X. Liu, L. Jia, R. Blatt, Y.-J. Day, G. W. Sullivan, J. Linden, and A. L. Tucker A1 Adenosine Receptor Activation Promotes Angiogenesis and Release of VEGF From Monocytes Circ. Res., November 26, 2007; 101(11): 1130 - 1138. [Abstract] [Full Text] [PDF]

				Y. Komi, O. Ohno, Y. Suzuki, M. Shimamura, K. Shimokado, K. Umezawa, and S. Kojima Inhibition of Tumor Angiogenesis by Targeting Endothelial Surface ATP Synthase with Sangivamycin Jpn. J. Clin. Oncol., November 1, 2007; 37(11): 867 - 873. [Abstract] [Full Text] [PDF]

				S. Merighi, A. Benini, P. Mirandola, S. Gessi, K. Varani, C. Simioni, E. Leung, S. Maclennan, P. G. Baraldi, and P. A. Borea Caffeine Inhibits Adenosine-Induced Accumulation of Hypoxia-Inducible Factor-1{alpha}, Vascular Endothelial Growth Factor, and Interleukin-8 Expression in Hypoxic Human Colon Cancer Cells Mol. Pharmacol., August 1, 2007; 72(2): 395 - 406. [Abstract] [Full Text] [PDF]

				X. Hua, C. J. Erikson, K. D. Chason, C. N. Rosebrock, D. A. Deshpande, R. B. Penn, and S. L. Tilley Involvement of A1 adenosine receptors and neural pathways in adenosine-induced bronchoconstriction in mice Am J Physiol Lung Cell Mol Physiol, July 1, 2007; 293(1): L25 - L32. [Abstract] [Full Text] [PDF]

				D. Ribatti, M. T. Conconi, and G. G. Nussdorfer Nonclassic Endogenous Novel Regulators of Angiogenesis Pharmacol. Rev., June 1, 2007; 59(2): 185 - 205. [Abstract] [Full Text] [PDF]

				S. Ryzhov, J. L. McCaleb, A. E. Goldstein, I. Biaggioni, and I. Feoktistov Role of Adenosine Receptors in the Regulation of Angiogenic Factors and Neovascularization in Hypoxia J. Pharmacol. Exp. Ther., February 1, 2007; 320(2): 565 - 572. [Abstract] [Full Text] [PDF]

				X. Hua, M. Kovarova, K. D. Chason, M. Nguyen, B. H. Koller, and S. L. Tilley Enhanced mast cell activation in mice deficient in the A2b adenosine receptor J. Exp. Med., January 22, 2007; 204(1): 117 - 128. [Abstract] [Full Text] [PDF]

				J. Linden Adenosine metabolism and cancer. Focus on "Adenosine downregulates DPPIV on HT-29 colon cancer cells by stimulating protein tyrosine phosphatases and reducing ERK1/2 activity via a novel pathway" Am J Physiol Cell Physiol, September 1, 2006; 291(3): C405 - C406. [Full Text] [PDF]

				S. Ryzhov, A. E. Goldstein, I. Biaggioni, and I. Feoktistov Cross-Talk between Gs- and Gq-Coupled Pathways in Regulation of Interleukin-4 by A2B Adenosine Receptors in Human Mast Cells Mol. Pharmacol., August 1, 2006; 70(2): 727 - 735. [Abstract] [Full Text] [PDF]

				Y. Chen, N. Hashiguchi, L. Yip, and W. G. Junger Hypertonic saline enhances neutrophil elastase release through activation of P2 and A3 receptors Am J Physiol Cell Physiol, April 1, 2006; 290(4): C1051 - C1059. [Abstract] [Full Text] [PDF]

				T. Nakayama, N. Mutsuga, L. Yao, and G. Tosato Prostaglandin E2 promotes degranulation-independent release of MCP-1 from mast cells J. Leukoc. Biol., January 1, 2006; 79(1): 95 - 104. [Abstract] [Full Text] [PDF]

				T. H. Adair Growth regulation of the vascular system: an emerging role for adenosine Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2005; 289(2): R283 - R296. [Abstract] [Full Text] [PDF]

				S. Gessi, K. Varani, S. Merighi, E. Cattabriga, C. Pancaldi, Y. Szabadkai, R. Rizzuto, K.-N. Klotz, E. Leung, S. Mac Lennan, et al. Expression, Pharmacological Profile, and Functional Coupling of A2B Receptors in a Recombinant System and in Peripheral Blood Cells Using a Novel Selective Antagonist Radioligand, [3H]MRE 2029-F20 Mol. Pharmacol., June 1, 2005; 67(6): 2137 - 2147. [Abstract] [Full Text] [PDF]

				A. Desai, C. Victor-Vega, S. Gadangi, M. C. Montesinos, C. C. Chu, and B. N. Cronstein Adenosine A2A Receptor Stimulation Increases Angiogenesis by Down-Regulating Production of the Antiangiogenic Matrix Protein Thrombospondin 1 Mol. Pharmacol., May 1, 2005; 67(5): 1406 - 1413. [Abstract] [Full Text] [PDF]

				J. Linden Adenosine in Tissue Protection and Tissue Regeneration Mol. Pharmacol., May 1, 2005; 67(5): 1385 - 1387. [Abstract] [Full Text] [PDF]

				C. Shibao, C. Arzubiaga, L. J. Roberts II, S. Raj, B. Black, P. Harris, and I. Biaggioni Hyperadrenergic Postural Tachycardia Syndrome in Mast Cell Activation Disorders Hypertension, March 1, 2005; 45(3): 385 - 390. [Abstract] [Full Text] [PDF]

				C. Feng, A. G. Mery, E. M. Beller, C. Favot, and J. A. Boyce Adenine Nucleotides Inhibit Cytokine Generation by Human Mast Cells through a Gs-Coupled Receptor J. Immunol., December 15, 2004; 173(12): 7539 - 7547. [Abstract] [Full Text] [PDF]

				I. Feoktistov, S. Ryzhov, H. Zhong, A. E. Goldstein, A. Matafonov, D. Zeng, and I. Biaggioni Hypoxia Modulates Adenosine Receptors in Human Endothelial and Smooth Muscle Cells Toward an A2B Angiogenic Phenotype Hypertension, November 1, 2004; 44(5): 649 - 654. [Abstract] [Full Text] [PDF]

				S. Ryzhov, A. E. Goldstein, A. Matafonov, D. Zeng, I. Biaggioni, and I. Feoktistov Adenosine-Activated Mast Cells Induce IgE Synthesis by B Lymphocytes: An A2B-Mediated Process Involving Th2 Cytokines IL-4 and IL-13 with Implications for Asthma J. Immunol., June 15, 2004; 172(12): 7726 - 7733. [Abstract] [Full Text] [PDF]

				S. E. Epstein, E. Stabile, T. Kinnaird, C. W. Lee, L. Clavijo, and M. S. Burnett Janus Phenomenon: The Interrelated Tradeoffs Inherent in Therapies Designed to Enhance Collateral Formation and Those Designed to Inhibit Atherogenesis Circulation, June 15, 2004; 109(23): 2826 - 2831. [Full Text] [PDF]

				J. Ahamed, R. T. Venkatesha, E. B. Thangam, and H. Ali C3a Enhances Nerve Growth Factor-Induced NFAT Activation and Chemokine Production in a Human Mast Cell Line, HMC-1 J. Immunol., June 1, 2004; 172(11): 6961 - 6968. [Abstract] [Full Text] [PDF]

				M. E. Olah and C. C. Caldwell Adenosine Receptors and Mammalian Toll-Like Receptors: Synergism in Macrophages Mol. Interv., October 1, 2003; 3(7): 370 - 374. [Abstract] [Full Text]

				V. Chhokar and A. L. Tucker Angiogenesis: Basic Mechanisms and Clinical Applications Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2003; 7(3): 253 - 280. [Abstract] [PDF]

				K. K Kalsi, A. H.Y Yuen, I. M Rybakowska, P. H Johnson, E. Slominska, E. J Birks, K. Kaletha, M. H Yacoub, and R. T Smolenski Decreased cardiac activity of AMP deaminase in subjects with the AMPD1 mutation--A potential mechanism of protection in heart failure Cardiovasc Res, September 1, 2003; 59(3): 678 - 684. [Abstract] [Full Text] [PDF]