Advertisement

Novel Endothelial-Mediated Responses Associated with Microcirculation and BBB Function

  • M. Spatz
  • Y. Chen
  • J. Bembry
  • F. A. Lenz
  • E. Shohami
  • Raphael Mechoulam
  • R. M. McCarron

Abstract

The importance of endothelial involvement in vascular relaxation induced by acetylcholine drew attention to the role of endothelial mediators in controlling vascular function (Furchgott and Zawadzki, 1980). Since this time, a great number of endothelial factors have been demonstrated to influence not only the vascular tone but also additional parameters including blood flow and blood-brain barrier (BBB) permeability (Rubanyi and Polokoff, 1994; Spatz, et al.,1995a; Gellai, et al.,1997; Thorin, et al.,1998). At the present time, there is substantial agreement that the mechanisms responsible for many of these events involve the interplay among a number of factors in either the circulation or produced locally. Studies in vivo and in vitro have shown that the most potent endothelialderived vasoactive substances, NO and ET-1, are primarily responsible for regulating the vascular reactivity (Gellai, et al.,1997; Bakker, et al.,1997). Our initial studies demonstrated that NO was involved in the postischemic hypoperfusion observed in animal models of cerebral ischemia (Spatz, et al.,1995b). This effect was related to increased levels of ET-1 in the cerebrospinal fluid (CSF). Treatment with ET-1 receptor antagonists abolished the hypoperfusion which resulted in neuronal protection from ischemic damage (Dawson, et al.,1999; Spatz, et al.,1996). These observations highlight the existence of the close relationship between these vasoactive factors and implicate their involvement in maintaining vascular tone and regulating circulation (e.g.,cerebral blood flow and blood pressure) as well as BBB function.

Keywords

Nitric Oxide Nitric Oxide Synthases Atrial Natriuretic Peptide Vasoactive Substance Human Brain Microvascular Endothelial Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ameri, A., 1999, The effects of cannabinoids on the brain. Prog. Neurobiol. 58: 315–384.PubMedCrossRefGoogle Scholar
  2. Bacic, F., Uematsu, S., McCarron, R.M., and Spatz, M., 1992, Secretion of immunoreactive endothelin-1 by capillary and microvascular endothelium of human brain. Neurochem. Res. 17: 699–702.PubMedCrossRefGoogle Scholar
  3. Bakker, E.N.T.P., van der Linden, P.J.W., and Sipkema, P., 1997, Endothelin-1-induced constriction inhibits nitric-oxide-mediated dilation in isolated rat resistance arteries. J. Vase. Res. 34: 418–424.CrossRefGoogle Scholar
  4. Boulanger, C., and Luscher, T., 1990, Release of endothelin from the porcine aorta. Inhibition by endothelin-derived nitric oxide. J. Clin. Invest. 85: 587–590.PubMedCrossRefGoogle Scholar
  5. Chen, Y., McCarron, R.M., Ohara, Y., Bembry, J., Azzam, N., Lenz, F.A., Shohami, E., Mechoulam, R., and Spatz, M., 2000, Human brain capillary endothelium. 2-arachidonoglycerol (endocannabinoid) interacts with endothelin-1. Cire. Res. 87: 323–327.CrossRefGoogle Scholar
  6. Chen, Y., McCarron, R.M., Bembry, J., Ruetzler, C, Azzam, N., Lenz, F.A., and Spatz, M., 1999, Nitric Oxide Modulates ET-1-induced Ca2+ mobilization and cytoskeletal F-actin filaments in human cerebromicrovascular endothelial cells. J. Cereb. Blood Flow Metab. 19: 133–138.PubMedCrossRefGoogle Scholar
  7. Cohen, R.A., and Vanhoutte, P.M., 1995, Endothelium-dependent hyperpolarization beyond nitric oxide and cyclic GMP. Circulation 92: 3337–3349.PubMedCrossRefGoogle Scholar
  8. Cornwell, T.L., and Lincoln, T.M., 1989, Regulation of intracellular Ca2+ levels in cultured vascular smooth muscle cells. Reduction of Ca2+ by atriopeptin and S-bromo-cyclic GMP is mediated by cyclic GMP-dependent protein kinase. J. Biol. Chem. 264: 1146–1155.PubMedGoogle Scholar
  9. Dawson, D.A., Sugano, H., McCarron, R.M., Hallenbeck, J.M., and Spatz, M., 1999, Endothelin receptor antagonist preserves microvascular perfusion and reduces ischemie brain damage following permanent focal ischemia. Neurochem. Res. 24: 1499–1505.PubMedCrossRefGoogle Scholar
  10. Di Marzo, V., 1998, Endocannabinoids’ and other fatty acid derivatives with cannabimimetic properties: biochemistry and possible physiopathological relevance. Biochim. Biophys. Acta. 1392: 153–175.PubMedCrossRefGoogle Scholar
  11. Faire, A.L., Riesco, A., Moliz, M., Egido, J., Casado, S., Hernando, L., and Caramelo, C., 1991, Inhibition by L-arginine of the endothelin-mediated increase in cytosolic calcium in human neutrophils. Biochem. Biophys. Res. Commun. 178: 884–891.CrossRefGoogle Scholar
  12. Furchgott, R.F., and Zawadzki, J.V., 1980, The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288: 373–376.PubMedCrossRefGoogle Scholar
  13. Gebremedhin, D., Lange, A.R., Campbell, W.B., Hillard, C.J., and Harder, D.R., 1999, Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit L-type Ca2+ channel current. Am. J. Physiol. 276: H2085–H2093.PubMedGoogle Scholar
  14. Gellai, M., De Wolf, R., Fletcher, T., and Nambi, P., 1997, Contribution of endogenous endothelin-1 to the maintenance of vascular tone: role of nitric oxide. Pharmacology 55: 299–308.PubMedCrossRefGoogle Scholar
  15. Goligorsky, M.A., Tsukahara, H., Magazine, H., Andersen, T.T., Malik, A.B., and Bahou, W.F., 1994, Termination of endothelin signaling: role of nitric oxide. J. Cell. Physiol. 158: 485–494.PubMedCrossRefGoogle Scholar
  16. Masaki, T., Vane, G.R., and Vanhoutte, P.M., 1994, International union of pharmacology nomenclature of endothelin receptors. Pharmac. Rev. 46: 137–142.Google Scholar
  17. Mechoulam, R., Ben-Shabat, S., Hanus, L., Ligumsky, M., Kaminski, N.E., Schatz, A.R., Gopher, A., Almog, S., Martin, B.R., and Compton, D.R., 1995, Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 50: 83–90.PubMedCrossRefGoogle Scholar
  18. Mechoulam, R., Fride, E., Ben-Shabat, S., Meiri, U., and Horowitz, M., 1998, Carbachol, an acetylcholine receptor agonist, enhances production in rat aorta of 2-arachidonoyl glycerol, a hypotensive endocannabinoid. Eur. J. Pharmacol. 362: R1–R3.PubMedCrossRefGoogle Scholar
  19. Molitoris, B.A., Leiser, J., and Wagner, M.C., 1997, Role of the actin cytoskeleton in ischemia-induced cell and repair. Pediatr. Nephrol. 11: 761–767.PubMedCrossRefGoogle Scholar
  20. Moncada, S., Palmer, R.M., and Higgs, E.A., 1991, Nitric oxide: physiology, pathophysiology, pharmacology. Pharmacol Rev. 43: 109–142.PubMedGoogle Scholar
  21. Okishio, M., Ohkawa, S., Ichimori, Y., and Kondo, K., 1992, Interaction between endothelium-derived relaxing factors, S-nitrosothiols, and endothelin-1 on Ca2+ mobilization in rat vascular smooth muscle cells. Biochem. Biophys. Res. Commun. 183: 849–855.PubMedCrossRefGoogle Scholar
  22. Piomelli, D., Giuffrida, A., Calignano, A., and Rodriguez de Fonseca, F., 2000, The endocannabinoid system as a target for therapeutic drugs. TIPS 21: 218–224.PubMedGoogle Scholar
  23. Quilley, J., Fulton, D., and McGiff, J.C., 1997, Hyperpolarizing factors. Biochem. Pharmacol. 54: 1059–1070.PubMedCrossRefGoogle Scholar
  24. Randall, M.D., and Kendall, D.A., 1998, Endocannabinoids: a new class of vasoactive substances. J. Trends. Pharmaco. Sci. 19: 55–58.CrossRefGoogle Scholar
  25. Rasmussen, H., 1983, Cellular calcium metabolism. Ann. Int. Med. 98: 809–816.PubMedGoogle Scholar
  26. Reinhard, M., Halbrugge, M., Scheer, U., Wiegand, C., Jockusch, B.M., and Walter, U., 1992, The 46/50 kDa phosphoprotein VASP purified from human platelets is a novel protein associated with actin filaments and focal contacts. EMBO J. 11: 2063–2070.PubMedGoogle Scholar
  27. Rubanyi, G.M., and Polokoff, M.A., 1994, Endothelins: molecular biology, biochemistry, pharmacology, physiology and pathophysiology. Pharmacol. Rev. 46: 325–415.PubMedGoogle Scholar
  28. Saijonmaa, O., Ristimaki, A., and Fyhrquist, F., 1990, Atrial natriuretic peptide, nitroglycerine, and nitroprusside reduce basal and stimulated endothelin production from cultured endothelial cells. Biochem. Biophys. Res. Commun. 173: 514–520.PubMedCrossRefGoogle Scholar
  29. Spatz, M., Kawai, N., Merkel, N., Bembry, J., and McCarron, R.M., 1997a, Functional properties of cultured endothelial cells derived from large microvessels of human brain. Am. J. Physiol. 272: C231–C239.PubMedGoogle Scholar
  30. Spatz, M., Stanimirovic, D.B., and McCarron, R.M., 1995a, Endothelin as a mediator of blood-brain barrier function. In New Concepts of Blood-Brain Barrier (J. Greenwood, ed), Plenum Press, Amsterdam, pp. 47–61.Google Scholar
  31. Spatz, M., Stanimirovic, D.B., Strasser, A., and McCarron, R.M., 1995b, Nitro-L-arginine augments the endothelin-1 content of cerebrospinal fluid induced by cerebral ischemia. Brain Res. 684: 99–102.PubMedCrossRefGoogle Scholar
  32. Spatz, M., Yamamoto, H., Yamamoto, T., and McCarron, R.M., 1997b, Effect of nitric oxide donors on ET-1 binding sites in human cerebrovascular endothelium. J. Cereb. Blood Flow Metab. 17(Suppl 1): S397.Google Scholar
  33. Spatz, M., Yasuma, Y., Strasser, A., and McCarron, R.M., 1996, Cerebral postischemic hypoperfusion is mediated by ETA receptors. Brain Res. 726: 242–246.PubMedCrossRefGoogle Scholar
  34. Stanimirovic, D., Yamamoto, T., Uematsu, S., and Spatz, M., 1994, Endothelin-1 receptor binding and cellular signal transduction in cultured human brain endothelial cells. J. Neurochem. 62: 592–601.PubMedCrossRefGoogle Scholar
  35. Sugiura, T., Kodaka, T., Kondo, S., Tonegawa, T., Nakane, S., Kishimoto, S., Yamashita, A., and Waku, K., 1996, 2-Arachidonoylglycerol, a putative endogenous cannabinoid receptor ligand, induces rapid, transient elevation of intracellular free Ca2+ in neuroblastoma x glioma hybrid NG108-15 cells. Biochem. Biophys. Res. Commun. 229: 58–64.PubMedCrossRefGoogle Scholar
  36. Sugiura, T., Kodaka, T., Nakane, S., Kishimoto, S., Kondo, S., and Waku, K., 1998, Detection of an endogenous cannabimimetic molecule, 2-arachidonoylglycerol, and cannabinoid CBl receptor mRNA in human vascular cells: Is 2-arachidonoylglycerol a possible vasomodulator? Biochem. Biophys. Res. Comm. 243: 838–843.PubMedCrossRefGoogle Scholar
  37. Thorin, E., Cernacek, P., and Dupuis, J., 1998, Endothelin-1 regulates tone of isolated small arteries in the rat: effect of hyperendothelinmia. Hypertension 31: 1035–1041.PubMedCrossRefGoogle Scholar
  38. Walsh, M.P., Kargacin, G.J., Kendrick-Jones, J., and Lincoln, T.M., 1995, Intracellular mechanisms involved in the regulation of vascular smooth muscle tone. Can. J. Physiol. Pharmacol. 73: 565–573.PubMedCrossRefGoogle Scholar
  39. Yanagisawa, M., Kurihara, H., Kimura, S., Tomobe, Y., Kobayashi, M., Mitsui, Y., Yazaki, Y., Goto, K., and Masaki, T., 1988, A novel potent vasoconstrictive peptide produced by endothelial cells. Nature, 332: 411–415.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • M. Spatz
    • 1
  • Y. Chen
    • 1
  • J. Bembry
    • 1
  • F. A. Lenz
    • 2
  • E. Shohami
    • 3
  • Raphael Mechoulam
    • 3
  • R. M. McCarron
    • 4
  1. 1.Stroke Branch, NINDS, NIHBethesdaUSA
  2. 2.Johns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Hebrew UniversityJerusalemIsrael
  4. 4.Resuscitative Medicine DepartmentNaval Medical Research CenterBethesdaUSA

Personalised recommendations