Skip to main content
SpringerLink
Log in

The Adrenergic System in Vascular Endothelial Cells

  • Chapter
  • First Online:
The Cardiovascular Adrenergic System

  • 787 Accesses

Abstract

The adrenergic system and vascular endothelium are strictly connected in the setting of molecular mechanisms aimed to regulate vascular functions. It is indeed well established that functional adrenergic receptors like α1/2 and β2 reside on the endothelial surface and participate in the intricate intracellular events that can favor alternatively vasodilation or vasoconstriction and inhibit or promote angiogenesis for example. Even though the endothelium possesses several receptor types able to transmit different kind of signals, the specificity and peculiarity of endothelium and adrenergic system relationship are witnessed by the ability of the endothelial cell to produce its own catecholamine and be always provided with sufficient adrenergic stimulation in order to accomplish its physiological functions. This chapter considers the most relevant knowledge in the adrenergic regulation of the endothelium and focuses on how alterations of endothelial adrenergic signaling can contribute to the development of disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Furchgott RF, Vanhoutte PM. Endothelium-derived relaxing and contracting factors. FASEB J. 1989;3:2007–18.

    CAS  PubMed  Google Scholar 

  2. Lusher JM, Salzman PM. Viral safety and inhibitor development associated with factor VIIIC ultra-purified from plasma in hemophiliacs previously unexposed to factor VIIIC concentrates. The monoclate study group. Semin Hematol. 1990;27:1–7.

    CAS  PubMed  Google Scholar 

  3. Schmidt HH, Walter U. NO at work. Cell. 1994;78:919–25.

    Article  CAS  PubMed  Google Scholar 

  4. Vanhoutte PM. Endothelial dysfunction in hypertension. J Hypertens Suppl. 1996;14:S83–93.

    Article  CAS  PubMed  Google Scholar 

  5. Sorriento D, Santulli G, Del Giudice C, Anastasio A, Trimarco B, Iaccarino G. Endothelial cells are able to synthesize and release catecholamines both in vitro and in vivo. Hypertension. 2012;60:129–136.

    Article  CAS  PubMed  Google Scholar 

  6. Ferro A, Queen LR, Priest RM, Xu B, Ritter JM, Poston L, Ward JP. Activation of nitric oxide synthase by beta 2-adrenoceptors in human umbilical vein endothelium in vitro. Br J Pharmacol. 1999;126:1872–1880.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Ciccarelli M, Sorriento D, Franco A, Fusco A, Del Giudice C, Annunziata R, Cipolletta E, Monti MG, Dorn GW 2nd, Trimarco B, Iaccarino G. Endothelial G protein-coupled receptor kinase 2 regulates vascular homeostasis through the control of free radical oxygen species. Arterioscler Thromb Vasc Biol. 2013;33:2415–24.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Campbell WB, Gauthier KM. Inducible endothelium-derived hyperpolarizing factor: role of the 15-lipoxygenase-EDHF pathway. J Cardiovasc Pharmacol. 2013;61:176–87.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Iaccarino G, Ciccarelli M, Sorriento D, Cipolletta E, Cerullo V, Iovino GL, Paudice A, Elia A, Santulli G, Campanile A, Arcucci O, Pastore L, Salvatore F, Condorelli G, Trimarco B. AKT participates in endothelial dysfunction in hypertension. Circulation. 2004;109:2587–93.

    Article  CAS  PubMed  Google Scholar 

  10. Iaccarino G, Cipolletta E, Fiorillo A, Annecchiarico M, Ciccarelli M, Cimini V, Koch WJ, Trimarco B. Beta(2)-adrenergic receptor gene delivery to the endothelium corrects impaired adrenergic vasorelaxation in hypertension. Circulation. 2002;106:349–355.

    Article  CAS  PubMed  Google Scholar 

  11. Iaccarino G, Ciccarelli M, Sorriento D, Galasso G, Campanile A, Santulli G, Cipolletta E, Cerullo V, Cimini V, Altobelli GG, Piscione F, Priante O, Pastore L, Chiariello M, Salvatore F, Koch WJ, Trimarco B. Ischemic neoangiogenesis enhanced by beta2-adrenergic receptor overexpression: a novel role for the endothelial adrenergic system. Circ Res. 2005;97:1182–89.

    Article  CAS  PubMed  Google Scholar 

  12. Ciccarelli M, Sorriento D, Cipolletta E, Santulli G, Fusco A, Zhou RH, Eckhart AD, Peppel K, Koch WJ, Trimarco B, Iaccarino G. Impaired neoangiogenesis in beta-adrenoceptor gene-deficient mice: restoration by intravascular human beta-adrenoceptor gene transfer and role of NFkappaB and CREB transcription factors. Br J Pharmacol. 2011;162:712–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Boer C, Scheffer GJ, de Lange JJ, Westerhof N, Sipkema P. Alpha-1-adrenoceptor stimulation induces nitric oxide release in rat pulmonary arteries. J Vasc Res. 1999;36:79–81.

    Article  CAS  PubMed  Google Scholar 

  14. Boulanger CM, Vanhoutte PM. G proteins and endothelium-dependent relaxations. J Vasc Res. 1997;34:175–85.

    Article  CAS  PubMed  Google Scholar 

  15. Guimaraes S, Moura D. Vascular adrenoceptors: an update. Pharmacol Rev. 2001;53:319–356.

    CAS  PubMed  Google Scholar 

  16. Brush JE Jr., Faxon DP, Salmon S, Jacobs AK, Ryan TJ. Abnormal endothelium-dependent coronary vasomotion in hypertensive patients. J Am Coll Cardiol. 1992;19:809–15.

    Article  PubMed  Google Scholar 

  17. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A. 1987;84:9265–69.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524–26.

    Article  CAS  PubMed  Google Scholar 

  19. Richard V, Tanner FC, Tschudi M, Luscher TF. Different activation of L-arginine pathway by bradykinin, serotonin, and clonidine in coronary arteries. Am J Physiol. 1990;259:H1433–9.

    CAS  PubMed  Google Scholar 

  20. Vanhoutte PM, Miller VM. Alpha 2-adrenoceptors and endothelium-derived relaxing factor. Am J Med. 1989;87:1S-5S.

    Article  CAS  PubMed  Google Scholar 

  21. Bockman CS, Gonzalez-Cabrera I, Abel PW. Alpha-2 adrenoceptor subtype causing nitric oxide-mediated vascular relaxation in rats. J Pharmacol Exp Ther. 1996;278:1235–43.

    CAS  PubMed  Google Scholar 

  22. Bockman CS, Jeffries WB, Abel PW. Binding and functional characterization of alpha-2 adrenergic receptor subtypes on pig vascular endothelium. J Pharmacol Exp Ther. 1993;267:1126–1133.

    CAS  PubMed  Google Scholar 

  23. Queen LR, Ji Y, Xu B, Young L, Yao K, Wyatt AW, Rowlands DJ, Siow RC, Mann GE, Ferro A. Mechanisms underlying beta2-adrenoceptor-mediated nitric oxide generation by human umbilical vein endothelial cells. J Physiol. 2006;576:585–94.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Lembo G, Iaccarino G, Vecchione C, Barbato E, Izzo R, Fontana D, Trimarco B. Insulin modulation of an endothelial nitric oxide component present in the alpha2- and beta-adrenergic responses in human forearm. J Clin Invest. 1997;100:2007–14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Izzo R, Cipolletta E, Ciccarelli M, Campanile A, Santulli G, Palumbo G, Vasta A, Formisano S, Trimarco B, Iaccarino G. Enhanced GRK2 expression and desensitization of betaAR vasodilatation in hypertensive patients. Clin Transl Sci. 2008;1:215–20.

    Article  CAS  PubMed  Google Scholar 

  26. Moncada S. Nitric oxide. J Hypertens Suppl. 1994;12:S35–9.

    CAS  PubMed  Google Scholar 

  27. Balligand JL, Kobzik L, Han X, Kaye DM, Belhassen L, O’Hara DS, Kelly RA, Smith TW, Michel T. Nitric oxide-dependent parasympathetic signaling is due to activation of constitutive endothelial (type III) nitric oxide synthase in cardiac myocytes. J Biol Chem. 1995;270:14582–14586.

    Article  CAS  PubMed  Google Scholar 

  28. Buxton BF, Jones CR, Molenaar P, Summers RJ. Characterization and autoradiographic localization of beta-adrenoceptor subtypes in human cardiac tissues. Br J Pharmacol. 1987;92:299–310.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Molenaar P, Malta E, Jones CR, Buxton BF, Summers RJ. Autoradiographic localization and function of beta-adrenoceptors on the human internal mammary artery and saphenous vein. Br J Pharmacol. 1988;95:225–33.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Wu KK. Regulation of endothelial nitric oxide synthase activity and gene expression. Ann N Y Acad Sci. 2002;962:122–30.

    Article  CAS  PubMed  Google Scholar 

  31. Bauer PM, Fulton D, Boo YC, Sorescu GP, Kemp BE, Jo H, Sessa WC. Compensatory phosphorylation and protein-protein interactions revealed by loss of function and gain of function mutants of multiple serine phosphorylation sites in endothelial nitric-oxide synthase. J Biol Chem. 2003;278:14841–9.

    Article  CAS  PubMed  Google Scholar 

  32. Fleming I, Busse R. Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am J Physiol Regul Integr Comp Physiol. 2003;284:R1–12.

    Google Scholar 

  33. Oriowo MA. Different atypical beta-adrenoceptors mediate isoprenaline-induced relaxation in vascular and non-vascular smooth muscles. Life Sci. 1995;56:PL269–75.

    Article  CAS  PubMed  Google Scholar 

  34. Brawley L, Shaw AM, MacDonald A. Beta 1-, beta 2- and atypical beta-adrenoceptor-mediated relaxation in rat isolated aorta. Br J Pharmacol. 2000;129:637–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Dawes M, Chowienczyk PJ, Ritter JM. Effects of inhibition of the L-arginine/nitric oxide pathway on vasodilation caused by beta-adrenergic agonists in human forearm. Circulation. 1997;95:2293–7.

    Article  CAS  PubMed  Google Scholar 

  36. Lands AM, Luduena FP, Buzzo HJ. Differentiation of receptors responsive to isoproterenol. Life Sci. 1967;6:2241–9.

    Article  CAS  PubMed  Google Scholar 

  37. Schneider JC, El Kebir D, Chereau C, Lanone S, Huang XL, De Buys Roessingh AS, Mercier JC, Dall’Ava-Santucci J, Dinh-Xuan AT. Involvement of Ca2+/calmodulin-dependent protein kinase II in endothelial NO production and endothelium-dependent relaxation. Am J Physiol Heart Circ Physiol. 2003;284:H2311–9.

    Article  CAS  PubMed  Google Scholar 

  38. Butt E, Bernhardt M, Smolenski A, Kotsonis P, Frohlich LG, Sickmann A, Meyer HE, Lohmann SM, Schmidt HH. Endothelial nitric-oxide synthase (type III) is activated and becomes calcium independent upon phosphorylation by cyclic nucleotide-dependent protein kinases. J Biol Chem. 2000;275:5179–87.

    Article  CAS  PubMed  Google Scholar 

  39. Bredt DS, Ferris CD, Snyder SH. Nitric oxide synthase regulatory sites. Phosphorylation by cyclic AMP-dependent protein kinase, protein kinase C, and calcium/calmodulin protein kinase; identification of flavin and calmodulin binding sites. J Biol Chem. 1992;267:10976–81.

    CAS  PubMed  Google Scholar 

  40. Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature. 1999;399:597–601.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999;399:601–05.

    Article  CAS  PubMed  Google Scholar 

  42. Michell BJ, Chen Z, Tiganis T, Stapleton D, Katsis F, Power DA, Sim AT, Kemp BE. Coordinated control of endothelial nitric-oxide synthase phosphorylation by protein kinase C and the cAMP-dependent protein kinase. J Biol Chem. 2001;276:17625–8.

    Article  CAS  PubMed  Google Scholar 

  43. Luo Z, Fujio Y, Kureishi Y, Rudic RD, Daumerie G, Fulton D, Sessa WC, Walsh K. Acute modulation of endothelial Akt/PKB activity alters nitric oxide-dependent vasomotor activity in vivo. J Clin Invest. 2000;106:493–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Isenovic E, Walsh MF, Muniyappa R, Bard M, Diglio CA, Sowers JR. Phosphatidylinositol 3-kinase may mediate isoproterenol-induced vascular relaxation in part through nitric oxide production. Metabolism. 2002;51:380–6.

    Article  CAS  PubMed  Google Scholar 

  45. Franke TF, Yang SI, Chan TO, Datta K, Kazlauskas A, Morrison DK, Kaplan DR, Tsichlis PN. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell. 1995;81:727–36.

    Article  CAS  PubMed  Google Scholar 

  46. Kohn AD, Kovacina KS, Roth RA. Insulin stimulates the kinase activity of RAC-PK, a pleckstrin homology domain containing ser/thr kinase. EMBO J. 1995;14:4288–95.

    PubMed Central  CAS  PubMed  Google Scholar 

  47. Burgering BM, Coffer PJ. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature. 1995;376:599–602.

    Article  CAS  PubMed  Google Scholar 

  48. Rubenstein RC, Linder ME, Ross EM. Selectivity of the beta-adrenergic receptor among Gs, Gi’s, and Go: assay using recombinant alpha subunits in reconstituted phospholipid vesicles. Biochemistry. 1991;30:10769–77.

    Article  CAS  PubMed  Google Scholar 

  49. Okamoto T, Murayama Y, Hayashi Y, Inagaki M, Ogata E, Nishimoto I. Identification of a Gs activator region of the beta 2-adrenergic receptor that is autoregulated via protein kinase A-dependent phosphorylation. Cell. 1991;67:723–30.

    Article  CAS  PubMed  Google Scholar 

  50. Zamah AM, Delahunty M, Luttrell LM, Lefkowitz RJ. Protein kinase A-mediated phosphorylation of the beta 2-adrenergic receptor regulates its coupling to Gs and Gi. Demonstration in a reconstituted system. J Biol Chem. 2002;277:31249–56.

    Article  CAS  PubMed  Google Scholar 

  51. Baillie GS, Sood A, McPhee I, Gall I, Perry SJ, Lefkowitz RJ, Houslay MD. beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi. Proc Natl Acad Sci U S A. 2003;100:940–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Jalali S, Li YS, Sotoudeh M, Yuan S, Li S, Chien S, Shyy JY. Shear stress activates p60src-Ras-MAPK signaling pathways in vascular endothelial cells. Arterioscler Thromb Vasc Biol. 1998;18:227–34.

    Article  CAS  PubMed  Google Scholar 

  53. Luttrell LM, Lefkowitz RJ. The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals. J Cell Sci. 2002;115:455–65.

    CAS  PubMed  Google Scholar 

  54. Nagao M, Kaziro Y, Itoh H. The Src family tyrosine kinase is involved in Rho-dependent activation of c-Jun N-terminal kinase by Galpha12. Oncogene. 1999;18:4425–34.

    Article  CAS  PubMed  Google Scholar 

  55. Xiao RP. Beta-adrenergic signaling in the heart: dual coupling of the beta2-adrenergic receptor to G(s) and G(i) proteins. Sci STKE. 2001;2001:re15.

    CAS  PubMed  Google Scholar 

  56. Ma YC, Huang J, Ali S, Lowry W, Huang XY. Src tyrosine kinase is a novel direct effector of G proteins. Cell. 2000;102:635–46.

    Article  CAS  PubMed  Google Scholar 

  57. Trochu JN, Leblais V, Rautureau Y, Beverelli F, Le Marec H, Berdeaux A, Gauthier C. Beta 3-adrenoceptor stimulation induces vasorelaxation mediated essentially by endothelium-derived nitric oxide in rat thoracic aorta. Br J Pharmacol. 1999;128:69–76.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Rautureau Y, Toumaniantz G, Serpillon S, Jourdon P, Trochu JN, Gauthier C. Beta 3-adrenoceptor in rat aorta: molecular and biochemical characterization and signalling pathway. Br J Pharmacol. 2002;137:153–61.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Freedman NJ, Liggett SB, Drachman DE, Pei G, Caron MG, Lefkowitz RJ. Phosphorylation and desensitization of the human beta 1-adrenergic receptor. Involvement of G protein-coupled receptor kinases and cAMP-dependent protein kinase. J Biol Chem. 1995;270:17953–61.

    Article  CAS  PubMed  Google Scholar 

  60. Rockman HA, Koch WJ, Lefkowitz RJ. Seven-transmembrane-spanning receptors and heart function. Nature. 2002;415:206–12.

    Article  CAS  PubMed  Google Scholar 

  61. Penela P, Ribas C, Mayor F Jr. Mechanisms of regulation of the expression and function of G protein-coupled receptor kinases. Cell Signal. 2003;15:973–81.

    Article  CAS  PubMed  Google Scholar 

  62. Premont RT, Inglese J, Lefkowitz RJ. Protein kinases that phosphorylate activated G protein-coupled receptors. FASEB J. 1995;9:175–82.

    CAS  PubMed  Google Scholar 

  63. Ferguson SS. Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol Rev. 2001;53:1–24.

    CAS  PubMed  Google Scholar 

  64. Pitcher JA, Freedman NJ, Lefkowitz RJ. G protein-coupled receptor kinases. Annu Rev Biochem. 1998;67:653–92.

    Article  CAS  PubMed  Google Scholar 

  65. Huang ZM, Gao E, Fonseca FV, Hayashi H, Shang X, Hoffman NE, Chuprun JK, Tian X, Tilley DG, Madesh M, Lefer DJ, Stamler JS, Koch WJ. Convergence of G protein-coupled receptor and S-nitrosylation signaling determines the outcome to cardiac ischemic injury. Sci Signal. 2013;6:ra95.

    PubMed Central  PubMed  Google Scholar 

  66. Liu S, Premont RT, Kontos CD, Zhu S, Rockey DC. A crucial role for GRK2 in regulation of endothelial cell nitric oxide synthase function in portal hypertension. Nat Med. 2005;11:952–8.

    Article  CAS  PubMed  Google Scholar 

  67. Taguchi K, Matsumoto T, Kamata K, Kobayashi T. G protein-coupled receptor kinase 2, with beta-arrestin 2, impairs insulin-induced Akt/endothelial nitric oxide synthase signaling in ob/ob mouse aorta. Diabetes. 2012;61:1978–85.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Zschauer AO, Sielczak MW, Smith DA, Wanner A. Norepinephrine-induced contraction of isolated rabbit bronchial artery: role of alpha 1- and alpha 2-adrenoceptor activation. J Appl Physiol. 1997;82:1918–25.

    Article  CAS  PubMed  Google Scholar 

  69. Filippi S, Parenti A, Donnini S, Granger HJ, Fazzini A, Ledda F. alpha(1D)-adrenoceptors cause endothelium-dependent vasodilatation in the rat mesenteric vascular bed. J Pharmacol Exp Ther. 2001;296:869–75.

    CAS  PubMed  Google Scholar 

  70. Angus JA, Cocks TM, Satoh K. The alpha adrenoceptors on endothelial cells. Fed Proc. 1986;45:2355–9.

    CAS  PubMed  Google Scholar 

  71. Bryan RM, Jr., Eichler MY, Swafford MW, Johnson TD, Suresh MS, Childres WF. Stimulation of alpha 2 adrenoceptors dilates the rat middle cerebral artery. Anesthesiology. 1996;85:82–90.

    Article  CAS  PubMed  Google Scholar 

  72. Flavahan NA, Shimokawa H, Vanhoutte PM. Pertussis toxin inhibits endothelium-dependent relaxations to certain agonists in porcine coronary arteries. J Physiol. 1989;408:549–60.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Miller VM, Flavahan NA, Vanhoutte PM. Pertussis toxin reduces endothelium-dependent and independent responses to alpha-2-adrenergic stimulation in systemic canine arteries and veins. J Pharmacol Exp Ther. 1991;257:290–3.

    CAS  PubMed  Google Scholar 

  74. Shimokawa H, Flavahan NA, Vanhoutte PM. Natural course of the impairment of endothelium-dependent relaxations after balloon endothelium removal in porcine coronary arteries. Possible dysfunction of a pertussis toxin-sensitive G protein. Circ Res. 1989;65:740–53.

    Article  CAS  PubMed  Google Scholar 

  75. Shimokawa H, Flavahan NA, Vanhoutte PM. Loss of endothelial pertussis toxin-sensitive G protein function in atherosclerotic porcine coronary arteries. Circulation. 1991;83:652–60.

    Article  CAS  PubMed  Google Scholar 

  76. Flavahan NA, Vanhoutte PM. G-proteins and endothelial responses. Blood Vessels. 1990;27:218–29.

    CAS  PubMed  Google Scholar 

  77. Freeman JE, Kuo WY, Drenger B, Barnett TN, Levine MA, Flavahan NA. Analysis of lysophophatidylcholine-induced endothelial dysfunction. J Cardiovasc Pharmacol. 1996;28:345–52.

    Article  CAS  PubMed  Google Scholar 

  78. Lembo G, Iaccarino G, Vecchione C, Barbato E, Morisco C, Monti F, Parrella L, Trimarco B. Insulin enhances endothelial alpha2-adrenergic vasorelaxation by a pertussis toxin mechanism. Hypertension. 1997;30:1128–34.

    Article  CAS  PubMed  Google Scholar 

  79. Miller VM, Barber DA. Modulation of endothelium-derived nitric oxide in canine femoral veins. Am J Physiol. 1996;271:H668–73.

    CAS  PubMed  Google Scholar 

  80. Cheng L, Yang C, Hsu L, Lin MT, Jen CJ, Chen H. Acute exercise enhances receptor-mediated endothelium-dependent vasodilation by receptor upregulation. J Biomed Sci. 1999;6:22–7.

    Article  CAS  PubMed  Google Scholar 

  81. Testa U, Pannitteri G, Condorelli GL. Vascular endothelial growth factors in cardiovascular medicine. J Cardiovasc Med (Hagerstown). 2008;9:1190–221.

    Article  Google Scholar 

  82. Papetti M, Herman IM. Mechanisms of normal and tumor-derived angiogenesis. Am J Physiol Cell Physiol. 2002;282:C947–70.

    Article  CAS  PubMed  Google Scholar 

  83. Carmeliet P, Collen D. Molecular basis of angiogenesis. Role of VEGF and VE-cadherin. Ann N Y Acad Sci. 2000;902:249–262 (discussion 262–244).

    Article  CAS  PubMed  Google Scholar 

  84. Rengo G, Zincarelli C, Femminella GD, Liccardo D, Pagano G, de Lucia C, Altobelli GG, Cimini V, Ruggiero D, Perrone-Filardi P, Gao E, Ferrara N, Lymperopoulos A, Koch WJ, Leosco D. Myocardial beta(2) -adrenoceptor gene delivery promotes coordinat cardiac adaptive remodelling and angiogenesis in heart failure. Br J Pharmacol. 2011;166:2348–61.

    Article  CAS  Google Scholar 

  85. Gupta K, Kshirsagar S, Li W, Gui L, Ramakrishnan S, Gupta P, Law PY, Hebbel RP. VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling. Exp Cell Res. 1999;247:495–504.

    Article  CAS  PubMed  Google Scholar 

  86. Philipp M, Hein L. Adrenergic receptor knockout mice: distinct functions of 9 receptor subtypes. Pharmacol Ther. 2004;101:65–74.

    Article  CAS  PubMed  Google Scholar 

  87. Axelrod J, Weinshilboum R. Catecholamines. N Engl J Med. 1972;287:237–42.

    Article  CAS  PubMed  Google Scholar 

  88. Lymperopoulos A, Rengo G, Koch WJ. Adrenal adrenoceptors in heart failure: fine-tuning cardiac stimulation. Trends Mol Med. 2007;13:503–11.

    Article  CAS  PubMed  Google Scholar 

  89. Josefsson E, Bergquist J, Ekman R, Tarkowski A. Catecholamines are synthesized by mouse lymphocytes and regulate function of these cells by induction of apoptosis. Immunology. 1996;88:140–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  90. Bergquist J, Silberring J. Identification of catecholamines in the immune system by electrospray ionization mass spectrometry. Rapid Commun Mass Spectrom. 1998;12:683–8.

    Article  CAS  PubMed  Google Scholar 

  91. Marino F, Cosentino M, Bombelli R, Ferrari M, Lecchini S, Frigo G. Endogenous catecholamine synthesis, metabolism storage, and uptake in human peripheral blood mononuclear cells. Exp Hematol. 1999;27:489–95.

    Article  CAS  PubMed  Google Scholar 

  92. Musso NR, Brenci S, Setti M, Indiveri F, Lotti G. Catecholamine content and in vitro catecholamine synthesis in peripheral human lymphocytes. J Clin Endocrinol Metab. 1996;81:3553–7.

    CAS  PubMed  Google Scholar 

  93. Spengler RN, Chensue SW, Giacherio DA, Blenk N, Kunkel SL. Endogenous norepinephrine regulates tumor necrosis factor-alpha production from macrophages in vitro. J Immunol. 1994;152:3024–31.

    CAS  PubMed  Google Scholar 

  94. Cosentino M, Fietta AM, Ferrari M, Rasini E, Bombelli R, Carcano E, Saporiti F, Meloni F, Marino F, Lecchini S. Human CD4+ CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop. Blood. 2007;109:632–42.

    Article  CAS  PubMed  Google Scholar 

  95. Engler KL, Rudd ML, Ryan JJ, Stewart JK, Fischer-Stenger K. Autocrine actions of macrophage-derived catecholamines on interleukin-1 beta. J Neuroimmunol. 2005;160:87–91.

    Article  CAS  PubMed  Google Scholar 

  96. Sorriento D, Santulli G, Del Giudice C, Anastasio A, Trimarco B, Iaccarino G. Endothelial cells are able to synthesize and release catecholamines both in vitro and in vivo. Hypertension. 2012;60:129–36.

    Article  CAS  PubMed  Google Scholar 

  97. Min J, Jin YM, Moon JS, Sung MS, Jo SA, Jo I. Hypoxia-induced endothelial NO synthase gene transcriptional activation is mediated through the tax-responsive element in endothelial cells. Hypertension. 2006;47:1189–96.

    Article  CAS  PubMed  Google Scholar 

  98. Goveia J, Stapor P, Carmeliet P. Principles of targeting endothelial cell metabolism to treat angiogenesis and endothelial cell dysfunction in disease. EMBO Mol Med. 2014. 25:1105–20

    Article  CAS  Google Scholar 

  99. Stein CM, Nelson R, Deegan R, He H, Wood M, Wood AJ. Forearm beta adrenergic receptor-mediated vasodilation is impaired, without alteration of forearm norepinephrine spillover, in borderline hypertension. J Clin Invest. 1995;96:579–85.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  100. Khalaila JM, Elami A, Caraco Y. Interaction between beta2 adrenergic receptor polymorphisms determines the extent of isoproterenol-induced vasodilatation ex vivo. Pharmacogenet Genomics. 2007;17:803–11.

    Article  CAS  PubMed  Google Scholar 

  101. Cockcroft JR, Gazis AG, Cross DJ, Wheatley A, Dewar J, Hall IP, Noon JP. Beta(2)-adrenoceptor polymorphism determines vascular reactivity in humans. Hypertension. 2000;36:371–5.

    Article  CAS  PubMed  Google Scholar 

  102. Barbato E, Berger A, Delrue L, Van Durme F, Manoharan G, Boussy T, Heyndrickx GR, De Bruyne B, Ciampi Q, Vanderheyden M, Wijns W, Bartunek J. GLU-27 variant of beta2-adrenergic receptor polymorphisms is an independent risk factor for coronary atherosclerotic disease. Atherosclerosis. 2007;194:e80–6.

    Article  CAS  PubMed  Google Scholar 

  103. Hindorff LA, Heckbert SR, Psaty BM, Lumley T, Siscovick DS, Herrington DM, Edwards KL, Tracy RP. beta(2)-Adrenergic receptor polymorphisms and determinants of cardiovascular risk: the cardiovascular health study. Am J Hypertens. 2005;18:392–7.

    Article  CAS  PubMed  Google Scholar 

  104. Cockcroft JR, Chowienczyk PJ, Brett SE, Chen CP, Dupont AG, Van Nueten L, Wooding SJ, Ritter JM. Nebivolol vasodilates human forearm vasculature: evidence for an L-arginine/NO-dependent mechanism. J Pharmacol Exp Ther. 1995;274:1067–71.

    CAS  PubMed  Google Scholar 

  105. Tzemos N, Lim PO, MacDonald TM. Nebivolol reverses endothelial dysfunction in essential hypertension: a randomized, double-blind, crossover study. Circulation. 2001;104:511–4.

    Article  CAS  PubMed  Google Scholar 

  106. Fratta Pasini A, Garbin U, Nava MC, Stranieri C, Davoli A, Sawamura T, Lo Cascio V, Cominacini L. Nebivolol decreases oxidative stress in essential hypertensive patients and increases nitric oxide by reducing its oxidative inactivation. J Hypertens. 2005;23:589–96.

    Article  PubMed  Google Scholar 

  107. Troost R, Schwedhelm E, Rojczyk S, Tsikas D, Frolich JC. Nebivolol decreases systemic oxidative stress in healthy volunteers. Br J Clin Pharmacol. 2000;50:377–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  108. Wojciechowski D, Papademetriou V. Beta-blockers in the management of hypertension: focus on nebivolol. Expert Rev Cardiovasc Ther. 2008;6:471–9.

    Article  CAS  PubMed  Google Scholar 

  109. Taguchi K, Kobayashi T, Matsumoto T, Kamata K. Dysfunction of endothelium-dependent relaxation to insulin via PKC-mediated GRK2/Akt activation in aortas of ob/ob mice. Am J Physiol Heart Circ Physiol. 2011;301:H571–83.

    Article  CAS  PubMed  Google Scholar 

  110. Leosco D, Iaccarino G, Cipolletta E, De Santis D, Pisani E, Trimarco V, Ferrara N, Abete P, Sorriento D, Rengo F, Trimarco B. Exercise restores beta-adrenergic vasorelaxation in ag rat carotid arteries. Am J Physiol Heart Circ Physiol. 2003;285:H369–74.

    Article  CAS  PubMed  Google Scholar 

  111. Taguchi K, Matsumoto T, Kamata K, Kobayashi T. Inhibitor of G protein-coupled receptor kinase 2 normalizes vascular endothelial function in type 2 diabetic mice by improving beta-arrestin 2 translocation and ameliorating Akt/eNOS signal dysfunction. Endocrinology. 2012;153:2985–96.

    Article  CAS  PubMed  Google Scholar 

  112. Napolitano R, Campanile A, Sarno L, Anastasio A, Maruotti GM, Morlando M, Trimarco B, Martinelli P, Iaccarino G. GRK2 levels in umbilical arteries of pregnancies complicated by gestational hypertension and preeclampsia. Am J Hypertens. 2012;25:366–71.

    Article  CAS  PubMed  Google Scholar 

  113. Jaber M, Koch WJ, Rockman H, Smith B, Bond RA, Sulik KK, Ross J, Jr., Lefkowitz RJ, Caron MG, Giros B. Essential role of beta-adrenergic receptor kinase 1 in cardiac development and function. Proc Natl Acad Sci U S A. 1996;93:12974–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  114. Fusco A, Santulli G, Sorriento D, Cipolletta E, Garbi C, Dorn GW, 2nd, Trimarco B, Feliciello A, Iaccarino G. Mitochondrial localization unveils a novel role for GRK2 in organelle biogenesis. Cell Signal. 2011;24:468–75.

    Google Scholar 

  115. Matkovich SJ, Diwan A, Klanke JL, Hammer DJ, Marreez Y, Odley AM, Brunskill EW, Koch WJ, Schwartz RJ, Dorn GW 2nd. Cardiac-specific ablation of G-protein receptor kinase 2 redefines its roles in heart development and beta-adrenergic signaling. Circ Res. 2006;99:996–1003.

    Article  CAS  PubMed  Google Scholar 

  116. Stevenson NL, Martin-Martin B, Freeman J, Kriston-Vizi J, Ketteler R, Cutler DF. G protein-coupled receptor kinase 2 moderates recruitment of THP-1 cells to the endothelium by limiting histamine-invoked Weibel-Palade body exocytosis. J Thromb Haemost. 2014;12:261–72.

    Article  PubMed Central  CAS  Google Scholar 

  117. Ogeng’o JA, Malek AA, Kiama SG. Structural organisation of tunica intima in the aorta of the goat. Folia Morphol (Warsz). 2010;69:164–9.

    Google Scholar 

  118. Lavezzi AM, Ottaviani G, Matturri L. Biology of the smooth muscle cells in human atherosclerosis. Apmis. 2005;113:112–21.

    Article  PubMed  Google Scholar 

  119. Hayashi T, Morishita E, Ohtake H, Oda Y, Asakura H, Nakao S. Expression of annexin II in experimental abdominal aortic aneurysms. Int J Hematol. 2009;90:336–42.

    Article  CAS  PubMed  Google Scholar 

  120. Greenwald SE. Ageing of the conduit arteries. J Pathol. 2007;211:157–72.

    Article  CAS  PubMed  Google Scholar 

  121. Rivas V, Carmona R, Munoz-Chapuli R, Mendiola M, Nogues L, Reglero C, Miguel-Martin M, Garcia-Escudero R, Dorn GW 2nd, Hardisson D, Mayor F Jr., Penela P. Developmental and tumoral vascularization is regulated by G protein-coupled receptor kinase 2. J Clin Invest. 2013;123:4714–30.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  122. Ribas C, Penela P, Murga C, Salcedo A, Garcia-Hoz C, Jurado-Pueyo M, Aymerich I, Mayor F Jr. The G protein-coupled receptor kinase (GRK) interactome: role of GRKs in GPCR regulation and signaling. Biochim Biophys Acta. 2007;1768:913–22.

    Article  CAS  PubMed  Google Scholar 

  123. Ciccarelli M, Cipolletta E, Iaccarino G. GRK2 at the control shaft of cellular metabolism. Curr Pharm Des. 2012;18:121–7.

    Article  CAS  PubMed  Google Scholar 

  124. Woodall MC, Ciccarelli M, Woodall BP, Koch WJ. G protein-coupled receptor kinase 2: a link between myocardial contractile function and cardiac metabolism. Circ Res. 2014;114:1661–70.

    Article  CAS  PubMed  Google Scholar 

  125. Koch WJ, Rockman HA, Samama P, Hamilton RA, Bond RA, Milano CA, Lefkowitz RJ. Cardiac function in mice overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitor. Science. 1995;268:1350–3.

    Article  CAS  PubMed  Google Scholar 

  126. Rengo G, Lymperopoulos A, Zincarelli C, Donniacuo M, Soltys S, Rabinowitz JE, Koch WJ. Myocardial adeno-associated virus serotype 6-betaARKct gene therapy improves cardiac function and normalizes the neurohormonal axis in chronic heart failure. Circulation. 2009;119:89–98.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  127. Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med. 2000;6:389–95.

    Article  CAS  PubMed  Google Scholar 

  128. Kanda S, Miyata Y, Kanetake H. Role of focal adhesion formation in migration and morphogenesis of endothelial cells. Cell Signal. 2004;16:1273–81.

    Article  CAS  PubMed  Google Scholar 

  129. Lutgendorf SK, DeGeest K, Dahmoush L, Farley D, Penedo F, Bender D, Goodheart M, Buekers TE, Mendez L, Krueger G, Clevenger L, Lubaroff DM, Sood AK, Cole SW. Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients. Brain Behav Immun. 2011;25:250–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  130. Schuller HM, Al-Wadei HA, Ullah MF, Plummer HK, 3rd. Regulation of pancreatic cancer by neuropsychological stress responses: a novel target for intervention. Carcinogenesis. 2012;33:191–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  131. Hermes GL, Delgado B, Tretiakova M, Cavigelli SA, Krausz T, Conzen SD, McClintock MK. Social isolation dysregulates endocrine and behavioral stress while increasing malignant burden of spontaneous mammary tumors. Proc Natl Acad Sci U S A. 2009;106:22393–98.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  132. Wong HP, Ho JW, Koo MW, Yu L, Wu WK, Lam EK, Tai EK, Ko JK, Shin VY, Chu KM, Cho CH. Effects of adrenaline in human colon adenocarcinoma HT-29 cells. Life Sci. 2011;88:1108–12.

    Article  CAS  PubMed  Google Scholar 

  133. Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, Jennings NB, Armaiz-Pena G, Bankson JA, Ravoori M, Merritt WM, Lin YG, Mangala LS, Kim TJ, Coleman RL, Landen CN, Li Y, Felix E, Sanguino AM, Newman RA, Lloyd M, Gershenson DM, Kundra V, Lopez-Berestein G, Lutgendorf SK, Cole SW, Sood AK. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med. 2006;12:939–44.

    Article  CAS  PubMed  Google Scholar 

  134. Sastry KS, Karpova Y, Prokopovich S, Smith AJ, Essau B, Gersappe A, Carson JP, Weber MJ, Register TC, Chen YQ, Penn RB, Kulik G. Epinephrine protects cancer cells from apoptosis via activation of cAMP-dependent protein kinase and BAD phosphorylation. J Biol Chem. 2007;282:14094–100.

    Article  CAS  PubMed  Google Scholar 

  135. Hassan S, Karpova Y, Baiz D, Yancey D, Pullikuth A, Flores A, Register T, Cline JM, D’Agostino R, Jr., Danial N, Datta SR, Kulik G. Behavioral stress accelerates prostate cancer development in mice. J Clin Invest. 2013;123:874–86.

    PubMed Central  CAS  PubMed  Google Scholar 

  136. Wu WK, Wong HP, Luo SW, Chan K, Huang FY, Hui MK, Lam EK, Shin VY, Ye YN, Yang YH, Cho CH. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone from cigarette smoke stimulates colon cancer growth via beta-adrenoceptors. Cancer Res. 2005;65:5272–77.

    Article  CAS  PubMed  Google Scholar 

  137. Lee JW, Shahzad MM, Lin YG, Armaiz-Pena G, Mangala LS, Han HD, Kim HS, Nam EJ, Jennings NB, Halder J, Nick AM, Stone RL, Lu C, Lutgendorf SK, Cole SW, Lokshin AE, Sood AK. Surgical stress promotes tumor growth in ovarian carcinoma. Clin Cancer Res. 2009;15:2695–702.

    Article  PubMed Central  PubMed  Google Scholar 

  138. Yang E, Boire A, Agarwal A, Nguyen N, O’Callaghan K, Tu P, Kuliopulos A, Covic L. Blockade of PAR1 signaling with cell-penetrating pepducins inhibits Akt survival pathways in breast cancer cells and suppresses tumor survival and metastasis. Cancer Res. 2009;69:6223–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  139. Yang EV, Kim SJ, Donovan EL, Chen M, Gross AC, Webster Marketon JI, Barsky SH, Glaser R. Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression. Brain Behav Immun. 2009;23:267–75.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  140. Madden KS, Szpunar MJ, Brown EB. β-Adrenergic receptors (beta-AR) regulate VEGF and IL-6 production by divergent pathways in high beta-AR-expressing breast cancer cell lines. Breast Cancer Res Treat 2011;130:747–58.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  141. Casini G, Dal Monte M, Fornaciari I, Filippi L, Bagnoli P. The beta-adrenergic system as a possible new target for pharmacologic treatment of neovascular retinal diseases. Prog Retin Eye Res. 2014;42:103–29

    Article  CAS  PubMed  Google Scholar 

  142. Lymperopoulos A. Ischemic emergency?: endothelial cells have their own “adrenaline shot” at hand. Hypertension. 2012;60:12–4.

    Article  CAS  PubMed  Google Scholar 

  143. Cockcroft JR, Pedersen ME. Beta-blockade: benefits beyond blood pressure reduction? J Clin Hypertens (Greenwich). 2012;14:112–20.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine and Surgery, University of Salerno, Salerno, Italy

    Michele Ciccarelli & Guido Iaccarino

  2. National Research Council, “Federico II” University of Naples, Naples, Italy

    Daniela Sorriento

Authors
  1. Michele Ciccarelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniela Sorriento
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guido Iaccarino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guido Iaccarino .

Editor information

Editors and Affiliations

  1. Dept. of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, Florida, USA

    Anastasios Lymperopoulos

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Ciccarelli, M., Sorriento, D., Iaccarino, G. (2015). The Adrenergic System in Vascular Endothelial Cells. In: Lymperopoulos, A. (eds) The Cardiovascular Adrenergic System. Springer, Cham. https://doi.org/10.1007/978-3-319-13680-6_3

Download citation

Publish with us

Policies and ethics

Search

Navigation