doi: 10.1161/CIRCRESAHA.107.170522
© 2008 American Heart Association, Inc.
Editorials |
Adenosine Prompts the Heart to Recruit Endothelial Progenitors
From the Department of Cell Biology, The Lerner Research Institute, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic Foundation, Ohio.
Correspondence to Jianzhong Shen, PhD, Department of Cell Biology, The Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail shenj{at}ccf.org
See related article, pages 356–363
Key Words: adenosine • endothelial progenitor cells • receptors • microvasculature
Adenosine has a long history of involvement in cardiac function. It was first purified from mammalian heart homogenates in 1929 by Drury and Szent-Györgyi,1 who reported a "suppressive" action of adenosine on the heart, including decreased heart beat rate and perfusion pressure,1 now termed bradycardia and coronary artery vasodilation, respectively. Based on a variety of experimental results from several laboratories, Berne et al proposed in the early 1960s that adenosine plays an important role in the adjustment of blood flow to the metabolic requirements of organs, including the heart, brain, and skeletal muscle.2 Numerous studies now support the hypothesis that adenosine can be directly released or generated from released ATP/ADP in the heart during ischemia, causing increased oxygen and nutrition supply by inducing coronary artery relaxation.3
Although adenosine exhibits reuptake via specific adenosine transporters, many, if not all, of the biological effects of adenosine are believed to be mediated by adenosine receptors (ARs), of which 4 subtypes (A1R, A2AR, A2BR, and A3R) have been cloned and pharmacologically characterized.4 The diverse physiological functions mediated by the different AR subtypes, particularly in the modulation of the cardiovascular system, have been confirmed by genetically engineered mice.4 Null mice have been generated for each of the AR subtypes, and none of the 4 ARs plays a critical role during development.4,5 Although each AR protein had been thought to exist in the cell membrane as a monomer, recent studies with recombinant expression systems have revealed that some of the AR subtypes heterodimerize with other G-protein coupled receptors. For example, A1R has been shown to heterodimerize with the P2Y1 receptor6 and with the D1 dopamine receptor,7 and A2AR heterodimerizes with the D2 dopamine receptor.8 However, it remains unknown whether any endogenous ARs exist as heterodimers in the cardiovascular system.
Adenosine is best known for its vasorelaxant effect, which has been intensively studied for the past several decades. Findings include: (1) in most blood vessels, including the coronary artery, adenosine is a potent vasodilator via activation of A2AR and/or A2BR, which are expressed by both the endothelium and smooth muscle;9 (2) in some branches of the pulmonary arteries and in renal afferent arterioles, adenosine functions as a potent vasoconstrictor, which is mediated exclusively by activation of A1R;9,10 (3) A1R is also expressed in coronary artery smooth muscle, which limits adenosine-induced coronary dilatation via A2AR and A2BR11; (4) it appears that vascular endothelial cells do not express appreciable A1R and A3R,12 which supports the view that adenosine-induced endothelium-dependent relaxation is mediated by A2AR and/or A2BR13; and finally (5) the A3R is expressed in some vascular smooth muscle, although its exact physiological function has not been conclusively determined.14
In addition to its acute effects, adenosine also has significant impact on vascular cell growth.15 For example, adenosine stimulates vascular endothelial cell growth through the A2 type adenosine receptors.16 In vascular smooth muscle cells, adenosine originally was solely described as antimitogenic via activation of A2BR.17 However, recent studies have demonstrated that adenosine functions as a mitogen in coronary artery smooth muscle cells via A1R.18,19 This apparent discrepancy was reconciled by experimental evidence indicating a differential expression profile of the four ARs in aorta versus coronary arteries.18,19 Thus, both the acute and chronic effects of adenosine are not uniform, partially because of the complexity of AR expression patterns in different blood vessels.
Accumulating evidence indicates that adenosine is also important in neovascularization, including angiogenesis and vasculogenesis, which in the heart, contributes to the well-known cardioprotective effects of adenosine in response to chronic ischemia or hypoxia.20 The proneovascularization action of adenosine has been documented to occur via multiple mechanisms. For example, adenosine is known to stimulate vascular endothelial cell proliferation, migration, and tube formation in vitro.15 In addition, adenosine stimulates synthesis of proangiogenic molecules, such as vascular endothelial growth factor, interleukin-8, and angiopoetin-1 in endothelial cells, monocytes, and macrophages.15,20 It is now clear that all 4 ARs are involved in the process of angiogenesis and/or vasculogenesis20; however, the contribution of the individual AR depends on the cell type and animal model used.21 Perhaps, the most convincing study in this respect is that of A2AR-knockout mice, which exhibit diminished blood vessel formation in healing skin wounds.22
In this issue of Circulation Research, Ryzhov et al23 have addressed a new question concerning the role of adenosine in endothelial progenitor cell (EPC) homing to cardiac endothelium (Figure). In this elegant study, the authors have made several significant observations: (1) stimulation of ARs for just 5 minutes in murine embryonic EPCs (eEPCs) and mouse cardiac microvascular endothelial cells (MCECs) increased eEPC adhesion to MCECs under static and flow conditions. A similar effect of adenosine was observed in the interaction of human adult culture-expanded EPCs and human cardiac microvascular endothelial cells; (2) these cell culture observations were confirmed in isolated mouse hearts that were perfused with adenosine, followed by an eEPC suspension, leading to increased eEPC retention in periendothelial areas; (3) the authors also determined that eEPCs and MCECs preferentially express functional A1R and A2BR, respectively (Figure), and that both receptors are involved in the enhanced cell–cell interaction; and, finally, (4) the authors showed that stimulation of AR in MCECs induced rapid cell surface expression of P-selectin, which binds to its ligand (P-selectin glycoprotein ligand-1) in eEPCs, leading to enhanced cell-cell adhesion (Figure). These original findings provided new insight into our understanding of the role of adenosine in vasculogenesis, a process in which EPC homing is crucial.
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It should be noted, however, that some of the present findings are not consistent with the literature. For example, in A2BR-deficient mice, the adhesiveness of the mesenteric arteries was increased, with increased expression of several adhesion molecules in endothelium, including P-selectin, E-selectin, and intracellular adhesion molecule-1,5 suggesting that A2BR activation in vivo may have a suppressive effect on cell adhesion to vascular endothelium, which contrasts with the main finding of the present study. Using a mouse skin wound model, others have demonstrated the predominant role of A2AR in promoting angiogenesis and vasculogenesis.22 These discrepancies may be explained by differences in tissues/organs; however, continued research using A2BR-deficient mice should assist in further testing of the model generated by the present study.
It is of great interest to know that eEPCs selectively express A1R (Figure), which plays a role in eEPC adhesion, although it appears not as significant as A2BR in cardiac endothelium as evidenced by a much lesser inhibitory effect of an A1R blocker than an A2BR blocker on eEPC adhesion.23 Future studies may address how activation of A1R affects the eEPC phenotype and whether increasing endogenous adenosine levels by suppressing adenosine degradation and/or uptake systems could boost the adhesion and retention of EPCs in experimental models. The postreceptor signaling mechanisms underlying A1R- and A2BR-mediated eEPC adhesion also remain to be determined.
In terms of pharmacological intervention, an A2BR-selective agonist may have some advantage over adenosine, which is known to cause bradycardia and atrioventricular blockage mediated by A1R. In a word, the present study23 provides a new concept of using adenosine as an alternative approach to enhance the efficacy of cell-based therapy for ischemic heart disease.
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Acknowledgments |
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Sources of Funding
Research by the authors is supported by NIH grant HL29582 (to P.E.D.) and a Morganthaler postdoctoral fellowship (to J.S.).
Disclosures
None.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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 Top References |
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1. Drury AN, Szent-Györgyi A. The physiological activity of adenine compounds with special reference to their action upon the mammalian heart. J Physiol. 1929; 68: 213–237.
2. Berne RM, Knabb RM, Ely SW, Rubio R. Adenosine in the local regulation of blood flow: a brief overview. Fed Proc. 1983; 42: 3136–3142.[Medline] [Order article via Infotrieve]
3. Feigl EO. Berne’s adenosine hypothesis of coronary blood flow control. Am J Physiol. 2004; 287: H1891–H1894.
4. Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev. 2001; 53: 527–552.
5. Yang D, Zhang Y, Nguyen HG, Koupenova M, Chauhan AK, Makitalo M, Jones MR, St Hilaire C, Seldin DC, Toselli P, Lamperti E, Schreiber BM, Gavras H, Wagner DD, Ravid K. The A2B adenosine receptor protects against inflammation and excessive vascular adhesion. J Clin Invest. 2006; 116: 1913–1923.[CrossRef][Medline] [Order article via Infotrieve]
6. Yoshioka K, Saitoh O, Nakata H. Heteromeric association creates a P2Y-like adenosine receptor. Proc Natl Acad Sci U S A. 2001; 98: 7617–7622.
7. Gines S, Hillion J, Torvinen M, Le Crom S, Casado V, Canela EI, Rondin S, Lew JY, Watson S, Zoli M, Agnati LF, Verniera P, Lluis C, Ferre S, Fuxe K, Franco R. Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes. Proc Natl Acad Sci U S A. 2000; 97: 8606–8611.
8. Canals M, Marcellino D, Fanelli F, Ciruela F, de Benedetti P, Goldberg SR, Neve K, Fuxe K, Agnati LF, Woods AS, Ferre S, Lluis C, Bouvier M, Franco R. Adenosine A2A-dopamine D2 receptor-receptor heteromerization: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer. J Biol Chem. 2003; 278: 46741–46749.
9. Tabrizchi R, Bedi S. Pharmacology of adenosine receptors in the vasculature. Pharmacol Ther. 2001; 91: 133–147.[CrossRef][Medline] [Order article via Infotrieve]
10. Hansen PB, Schnermann J. Vasoconstrictor and vasodilator effects of adenosine in the kidney. Am J Physiol. 2003; 285: F590–F599.
11. Tawfik HE, Teng B, Morrison RR, Schnermann J, Mustafa SJ. Role of A1 adenosine receptor in the regulation of coronary flow. Am J Physiol. 2006; 291: H467–H472.
12. Feoktistov I, Goldstein AE, Ryzhov S, Zeng D, Belardinelli L, Voyno-Yasenetskaya T, Biaggioni I. Differential expression of adenosine receptors in human endothelial cells: role of A2B receptors in angiogenic factor regulation. Circ Res. 2002; 90: 531–538.
13. Olanrewaju HA, Qin W, Feoktistov I, Scemama JL, Mustafa SJ. Adenosine A2A and A2B receptors in cultured human and porcine coronary artery endothelial cells. Am J Physiol. 2000; 279: H650–H656.
14. Linden J. Autoregulation of cyclic AMP in vascular smooth muscle: a role for adenosine receptors. Mol Pharmacol. 2002; 62: 969–970.
15. Adair TH. Growth regulation of the vascular system: an emerging role for adenosine. Am J Physiol. 2005; 289: R283–R296.[CrossRef]
16. Dubey RK, Gillespie DG, Jackson EK. A2B adenosine receptors stimulate growth of porcine and rat arterial endothelial cells. Hypertension. 2002; 39: 530–535.
17. Dubey RK, Gillespie DG, Shue H, Jackson EK. A2b receptors mediate antimitogenesis in vascular smooth muscle cells. Hypertension. 2000; 35: 267–272.
18. Shen J, Halenda SP, Wilden PA, Sturek M. Novel mitogenic effect of adenosine on coronary artery smooth muscle cells: role for the A1 adenosine receptor. Circ Res. 2005; 96: 982–990.
19. Shen J, Halenda SP, Sturek M, Wilden PA. Cell-signaling evidence for adenosine stimulation of coronary smooth muscle proliferation via the A1 adenosine receptor. Circ Res. 2005; 97: 574–582.
20. Auchampach JA. Adenosine receptors and angiogenesis. Circ Res. 2007; 101: 1075–1077.
21. Clark AN, Youkey R, Liu X, Jia L, Blatt R, Day YJ, Sullivan GW, Linden J, Tucker AL. A1 adenosine receptor activation promotes angiogenesis and release of VEGF from monocytes. Circ Res. 2007; 101: 1130–1138.
22. Montesinos MC, Desai A, Chen JF, Yee H, Schwarzschild MA, Fink JS, Cronstein BN. Adenosine promotes wound healing and mediates angiogenesis in response to tissue injury via occupancy of A2A receptors. Am J Pathol. 2002; 160: 2009–1018.
23. Ryzhov S, Solenkova NV, Goldstein AE, Lamparter M, Fleenor T, Young PP, Greelish JP, Byrne JG, Vaughan DE, Biaggioni I, Hatzopoulos AK, Feoktistov I. Adenosine receptor–mediated adhesion of endothelial progenitors to cardiac microvascular endothelial cells. Circ Res. 2008; 102: 356–363.
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