Abstract
Endothelium-derived relaxing factors (EDRFs), including nitric oxide (NO), prostacyclin (PGI2), and endothelium-derived hyperpolarizing factor (EDHF), play pivotal roles in regulating vascular tone. Reduced EDRFs cause impaired endothelium-dependent vasorelaxation, or endothelial dysfunction. Impaired endothelium-dependent vasorelaxation in response to acetylcholine (ACh) is consistently observed in conduit vessels in human patients and experimental animal models of hypertension. Because small resistance arteries are known to produce more than one type of EDRF, the mechanism(s) mediating endothelium-dependent vasorelaxation in small resistance arteries may be different from that observed in conduit vessels under hypertensive conditions, where vasorelaxation is mainly dependent on NO. EDHF has been described as one of the principal mediators of endothelium-dependent vasorelaxation in small resistance arteries in normotensive animals. Furthermore, EDHF appears to become the predominant endothelium-dependent vasorelaxation pathway when the endothelial NO synthase (NOS3)/NO pathway is absent, as in NOS3-knockout mice, whereas some studies have shown that the EDHF pathway is dysfunctional in experimental models of hypertension. This article reviews our current knowledge regarding EDRFs in small arteries under normotensive and hypertensive conditions.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
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.
Vanhoutte, P.M. (1989) Endothelium and control of vascular function. State of the Art lecture. Hypertension, 13, 658–667.
Luscher, T.F. and Barton, M. (1997) Biology of the endothelium. Clin. Cardiol., 20, II-3–10.
Palmer, R.M., Ferrige, A.G. and Moncada, S. (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature, 327, 524–526.
Dudzinski, D.M., Igarashi, J., Greif, D. and Michel, T. (2006) The regulation and pharmacology of endothelial nitric oxide synthase. Annu. Rev. Pharmacol. Toxicol., 46, 235–276.
Oelze, M., Mollnau, H., Hoffmann, N., Warnholtz, A., Bodenschatz, M., Smolenski, A., Walter, U., Skatchkov, M., Meinertz, T. and Munzel, T. (2000) Vasodilator-stimulated phosphoprotein serine 239 phosphorylation as a sensitive monitor of defective nitric oxide/cGMP signaling and endothelial dysfunction. Circ. Res., 87, 999–1005.
Halbrugge, M., Friedrich, C., Eigenthaler, M., Schanzenbächer, P. and Walter, U. (1990) Stoichiometric and reversible phosphorylation of a 46-kDa protein in human platelets in response to cGMP- and cAMP-elevating vasodilators. J. Biol. Chem., 265, 3088–3093.
Reinhard, M., Halbrügge, 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.
Smolenski, A., Bachmann, C., Reinhard, K., Hönig-Liedl, P., Jarchau, T., Hoschuetzky, H. and Walter, U. (1998) Analysis and regulation of vasodilator-stimulated phosphoprotein serine 239 phosphorylation in vitro and in intact cells using a phosphospecific monoclonal antibody. J. Biol. Chem., 273, 20029–20035.
Chen, L., Daum, G., Chitaley, K., Coats, S.A., Bowen-Pope, D.F., Eigenthaler, M., Thumati, N.R., Walter, U. and Clowes, A.W. (2004) Vasodilator-stimulated phosphoprotein regulates proliferation and growth inhibition by nitric oxide in vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol., 24, 1403–1408.
Aszódi, A., Pfeifer, A., Ahmad, M., Glauner, M., Zhou, X.H., Ny, L., Andersson, K.E., Kehrel, B., Offermanns, S. and Fassler, R. (1999) The vasodilator-stimulated phosphoprotein (VASP) is involved in cGMP- and cAMP-mediated inhibition of agonist-induced platelet aggregation, but is dispensable for smooth muscle function. EMBO J., 18, 37–48.
Fleming, I. and Busse, R. (2003) Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am. J. Physiol. Regul. Integr. Comp. Physiol., 284, R1–12.
Kukovetz, W.R., Holzmann, S., Wurm, A. and Pöch, G. (1979) Prostacyclin increases cAMP in coronary arteries. J. Cyclic Nucleotide Res., 5, 469–476.
Chang, J., Musser, J.H. and McGregor, H. (1987) Phospholipase A2: function and pharmacological regulation. Biochem. Pharmacol., 36, 2429–2436.
Imig, J.D., Zou, A.P., Stec, D.E., Harder, D.R., Falck, J.R. and Roman, R.J. (1996) Formation and actions of 20-hydroxyeicosatetraenoic acid in rat renal arterioles. Am. J. Physiol., 270, R217–227.
Bunting, S., Moncada, S. and Vane, J.R. (1983) The prostacyclin--thromboxane A2 balance: pathophysiological and therapeutic implications. Br. Med. Bull., 39, 271–276.
Vanhoutte, P.M. (1987) Vascular physiology: the end of the quest? Nature, 327, 459–460.
Chen, G., Suzuki, H. and Weston, A.H. (1988) Acetylcholine releases endothelium-derived hyperpolarizing factor and EDRF from rat blood vessels. Br. J. Pharmacol., 95, 1165–1174.
Félétou, M. and Vanhoutte, P.M. (2006) Endothelium-derived hyperpolarizing factor: where are we now? Arterioscler. Thromb. Vasc. Biol., 26, 1215–1225.
Tomioka, H., Hattori, Y., Fukao, M., Sato, A., Liu, M., Sakuma, I., Kitabatake, A. and Kanno, M. (1999) Relaxation in different-sized rat blood vessels mediated by endothelium-derived hyperpolarizing factor: importance of processes mediating precontractions. J. Vasc. Res., 36, 311–320.
Huang, A., Sun, D., Smith, C.J., Connetta, J.A., Shesely, E.G., Koller, A. and Kaley, G. (2000) In eNOS knockout mice skeletal muscle arteriolar dilation to acetylcholine is mediated by EDHF. Am. J. Physiol. Heart Circ. Physiol., 278, H762–768.
Jackson, W.F. (2000) Ion channels and vascular tone. Hypertension, 35, 173–178.
Vanhoutte, P.M. (2004) Endothelium-dependent hyperpolarizations: the history. Pharmacol. Res., 49, 503–508.
Edwards, G., Dora, K.A., Gardener, M.J., Garland, C.J. and Weston, A.H. (1998) K+ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature, 396, 269–272.
Taylor, H.J., Chaytor, A.T., Evans, W.H. and Griffith, T.M. (1998) Inhibition of the gap junctional component of endothelium-dependent relaxations in rabbit iliac artery by 18-alpha glycyrrhetinic acid. Br. J. Pharmacol., 125, 1–3.
Edwards, G., Félétou, M., Gardener, M.J., Thollon, C., Vanhoutte, P.M. and Weston, A.H. (1999) Role of gap junctions in the responses to EDHF in rat and guinea-pig small arteries. Br. J. Pharmacol., 128, 1788–1794.
Mather, S., Dora, K.A., Sandow, S.L., Winter, P. and Garland, C.J. (2005) Rapid endothelial cell-selective loading of connexin 40 antibody blocks endothelium-derived hyperpolarizing factor dilation in rat small mesenteric arteries. Circ. Res., 97, 399–407.
Kansui, Y., Fujii, K., Nakamura, K., Goto, K., Oniki, H., Abe, I., Shibata, Y. and Iida, M. (2004) Angiotensin II receptor blockade corrects altered expression of gap junctions in vascular endothelial cells from hypertensive rats. Am. J. Physiol. Heart Circ. Physiol., 287, H216–224.
Campbell, W.B. and Harder, D.R. (1999) Endothelium-derived hyperpolarizing factors and vascular cytochrome P450 metabolites of arachidonic acid in the regulation of tone. Circ. Res., 84, 484–488.
Fisslthaler, B., Popp, R., Kiss, L., Potente, M., Harder, D.R., Fleming, I. and Busse, R. (1999) Cytochrome P450 2C is an EDHF synthase in coronary arteries. Nature, 401, 493–497.
Nithipatikom, K., Pratt, P.F. and Campbell, W.B. (2000) Determination of EETs using microbore liquid chromatography with fluorescence detection. Am. J. Physiol. Heart Circ. Physiol., 279, H857–862.
Campbell, W.B., Falck, J.R. and Gauthier, K. (2001) Role of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factor in bovine coronary arteries. Med. Sci. Monit., 7, 578–584.
Pratt, P.F., Li, P., Hillard, C.J., Kurian, J. and Campbell, W.B. (2001) Endothelium-independent, ouabain-sensitive relaxation of bovine coronary arteries by EETs. Am. J. Physiol. Heart Circ. Physiol., 280, H1113–1121.
Li, P.L. and Campbell, W.B. (1997) Epoxyeicosatrienoic acids activate K+ channels in coronary smooth muscle through a guanine nucleotide binding protein. Circ. Res., 80, 877–884.
Imig, J.D., Inscho, E.W., Deichmann, P.C., Reddy, K.M. and Falck, J.R. (1999) Afferent arteriolar vasodilation to the sulfonimide analog of 11, 12-epoxyeicosatrienoic acid involves protein kinase A. Hypertension, 33, 408–413.
Earley, S., Heppner, T.J., Nelson, M.T. and Brayden, J.E. (2005) TRPV4 forms a novel Ca2+ signaling complex with ryanodine receptors and BKCa channels. Circ. Res., 97, 1270–1279.
Coats, P., Johnston, F., MacDonald, J., McMurray, J.J. and Hillier, C. (2001) Endothelium-derived hyperpolarizing factor: identification and mechanisms of action in human subcutaneous resistance arteries. Circulation, 103, 1702–1708.
Ardanaz, N. and Pagano, P.J. (2006) Hydrogen peroxide as a paracrine vascular mediator: regulation and signaling leading to dysfunction. Exp. Biol. Med. (Maywood), 231, 237–251.
Shimokawa, H. and Morikawa, K. (2005) Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in animals and humans. J. Mol. Cell. Cardiol., 39, 725–732.
Gao, Y.J., Hirota, S., Zhang, D.W., Janssen, L.J. and Lee, R.M. (2003) Mechanisms of hydrogen-peroxide-induced biphasic response in rat mesenteric artery. Br. J. Pharmacol., 138, 1085–1092.
Matoba, T., Shimokawa, H., Nakashima, M., Hirakawa, Y., Mukai, Y., Hirano, K., Kanaide, H. and Takeshita, A. (2000) Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice. J. Clin. Invest., 106, 1521–1530.
Katusic, Z.S. (1996) Superoxide anion and endothelial regulation of arterial tone. Free Radical Biol. Med., 20, 443–448.
Sullivan, J.C., Pollock, D.M. and Pollock, J.S. (2002) Altered nitric oxide synthase 3 distribution in mesenteric arteries of hypertensive rats. Hypertension, 39, 597–602.
Nava, E., Llinás, M.T., Gonzalez, J.D. and Salazar, F.J. (1996) Nitric oxide synthase activity in renal cortex and medulla of normotensive and spontaneously hypertensive rats. Am. J. Hypertens., 9, 1236–1239.
Hink, U., Li, H., Mollnau, H., Oelze, M., Matheis, E., Hartmann, M., Skatchkov, M., Thaiss, F., Stahl, R.A., Warnholtz, A., Meinertz, T., Griendling, K., Harrison, D.G., Forstermann, U. and Munzel, T. (2001) Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ. Res., 88, E14–22.
Laursen, J.B., Somers, M., Kurz, S., McCann, L., Warnholtz, A., Freeman, B.A., Tarpey, M., Fukai, T. and Harrison, D.G. (2001) Endothelial regulation of vasomotion in apoE-deficient mice: implications for interactions between peroxynitrite and tetrahydrobiopterin. Circulation, 103, 1282–1288.
Forstermann, U. and Munzel, T. (2006) Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation, 113, 1708–1714.
Gallego, M.J., Lopez Farre, A., Riesco, A., Monton, M., Grandes, S.M., Barat, A., Hernando, L., Casado, S. and Caramelo, C.A. (1993) Blockade of endothelium-dependent responses in conscious rats by cyclosporin A: effect of L-arginine. Am. J. Physiol., 264, H708–714.
Lee, M.Y., Jung, B.I., Chung, S.M., Bae, O.N., Lee, J.Y., Park, J.D., Yang, J.S., Lee, H. and Chung, J.H. (2003) Arsenic-induced dysfunction in relaxation of blood vessels. Environ. Health Perspect., 111, 513–517.
Lüscher, T.F. (1994) The endothelium in hypertension: bystander, target or mediator? J. Hypertens. Suppl., 12, S105–116.
Taddei, S., Virdis, A., Mattei, P. and Salvetti, A. (1993) Vasodilation to acetylcholine in primary and secondary forms of human hypertension. Hypertension, 21, 929–933.
Linder, L., Kiowski, W., Buhler, F.R. and Luscher, T.F. (1990) Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo. Blunted response in essential hypertension. Circulation, 81, 1762–1767.
Treasure, C.B., Klein, J.L., Vita, J.A., Manoukian, S.V., Renwick, G.H., Selwyn, A.P., Ganz, P. and Alexander, R.W. (1993) Hypertension and left ventricular hypertrophy are associated with impaired endothelium-mediated relaxation in human coronary resistance vessels. Circulation, 87, 86–93.
Hongo, K., Nakagomi, T., Kassell, N.F., Sasaki, T., Lehman, M., Vollmer, D.G., Tsukahara, T., Ogawa, H. and Torner, J. (1988) Effects of aging and hypertension on endothelium-dependent vascular relaxation in rat carotid artery. Stroke, 19, 892–897.
Dohi, Y., Thiel, M.A., Buhler, F.R. and Luscher, T.F. (1990) Activation of endothelial L-arginine pathway in resistance arteries. Effect of age and hypertension. Hypertension, 16, 170–179.
Lüscher, T.F., Vanhoutte, P.M. and Raij, L. (1987) Antihypertensive treatment normalizes decreased endothelium-dependent relaxations in rats with salt-induced hypertension. Hypertension, 9, III193–197.
Takase, H., Moreau, P., Küng, C.F., Nava, E. and Luscher, T.F. (1996) Antihypertensive therapy prevents endothelial dysfunction in chronic nitric oxide deficiency. Effect of verapamil and trandolapril. Hypertension, 27, 25–31.
Luscher, T.F., Dohi, Y. and Tschudi, M. (1992) Endothelium-dependent regulation of resistance arteries: alterations with aging and hypertension. J. Cardiovasc. Pharmacol., 19 Suppl 5, S34–42.
Taddei, S., Virdis, A., Mattei, P., Arzilli, F. and Salvetti, A. (1992) Endothelium-dependent forearm vasodilation is reduced in normotensive subjects with familial history of hypertension. J. Cardiovasc. Pharmacol., 20 Suppl 12, S193–195.
Sim, M.K. and Singh, M. (1987) Decreased responsiveness of the aortae of hypertensive rats to acetylcholine, histamine and noradrenaline. Br. J. Pharmacol., 90, 147–150.
Somers, M.J., Mavromatis, K., Galis, Z.S. and Harrison, D.G. (2000) Vascular superoxide production and vasomotor function in hypertension induced by deoxycorticosterone acetatesalt. Circulation, 101, 1722–1728.
Bennett, M.A., Watt, P.A. and Thurston, H. (1993) Impaired endothelium-dependent relaxation in two-kidney, one clip Goldblatt hypertension: effect of vasoconstrictor prostanoids. J. Hypertens. Suppl., 11, S134–135.
Laursen, J.B., Rajagopalan, S., Galis, Z., Tarpey, M., Freeman, B.A. and Harrison, D.G. (1997) Role of superoxide in angiotensin II-induced but not catecholamine-induced hypertension. Circulation, 95, 588–593.
White, R.M., Rivera, C.O. and Davison, C.B. (1996) Differential contribution of endothelial function to vascular reactivity in conduit and resistance arteries from deoxycorticosteronesalt hypertensive rats. Hypertension, 27, 1245–1253.
Pu, Q., Touyz, R.M. and Schiffrin, E.L. (2002) Comparison of angiotensin-converting enzyme (ACE), neutral endopeptidase (NEP) and dual ACE/NEP inhibition on blood pressure and resistance arteries of deoxycorticosterone acetate-salt hypertensive rats. J. Hypertens., 20, 899–907.
Li, J. and Bukoski, R.D. (1993) Endothelium-dependent relaxation of hypertensive resistance arteries is not impaired under all conditions. Circ. Res., 72, 290–296.
Fujii, K., Tominaga, M., Ohmori, S., Kobayashi, K., Koga, T., Takata, Y. and Fujishima, M. (1992) Decreased endothelium-dependent hyperpolarization to acetylcholine in smooth muscle of the mesenteric artery of spontaneously hypertensive rats. Circ. Res., 70, 660–669.
Virdis, A., Neves, M.F., Amiri, F., Viel, E., Touyz, R.M. and Schiffrin, E.L. (2002) Spironolactone improves angiotensin-induced vascular changes and oxidative stress. Hypertension, 40, 504–510.
Wang, D., Chabrashvili, T., Borrego, L., Aslam, S. and Umans, J.G. (2006) Angiotensin II infusion alters vascular function in mouse resistance vessels: roles of O and endothelium. J. Vasc. Res., 43, 109–119.
Deng, L.Y., Li, J.S. and Schiffrin, E.L. (1995) Endothelium-dependent relaxation of small arteries from essential hypertensive patients: mechanisms and comparison with normotensive subjects and with responses of vessels from spontaneously hypertensive rats. Clin. Sci. (Lond), 88, 611–622.
Rizzoni, D., Porteri, E., Castellano, M., Bettoni, G., Muiesan, M.L., Muiesan, P., Giulini, S.M. and Agabiti-Rosei, E. (1996) Vascular hypertrophy and remodeling in secondary hypertension. Hypertension, 28, 785–790.
Cockcroft, J.R., Chowienczyk, P.J., Benjamin, N. and Ritter, J.M. (1994) Preserved endothelium-dependent vasodilatation in patients with essential hypertension. N. Engl. J. Med., 330, 1036–1040.
Bruning, T.A., Chang, P.C., Hendriks, M.G., Vermeij, P., Pfaffendorf, M. and van Zwieten, P.A. (1995) In vivo characterization of muscarinic receptor subtypes that mediate vasodilatation in patients with essential hypertension. Hypertension, 26, 70–77.
Thybo, N.K., Mulvany, M.J., Jastrup, B., Nielsen, H. and Aalkjaer, C. (1996) Some pharmacological and elastic characteristics of isolated subcutaneous small arteries from patients with essential hypertension. J. Hypertens., 14, 993–998.
Furchgott, R.F. and Vanhoutte, P.M. (1989) Endothelium-derived relaxing and contracting factors. FASEB J., 3, 2007–2018.
Garland, C.J., Plane, F., Kemp, B.K. and Cocks, T.M. (1995) Endothelium-dependent hyperpolarization: a role in the control of vascular tone. Trends Pharmacol. Sci., 16, 23–30.
Kang, K.T., Sullivan, J.C., Sasser, J.M., Imig, J.D. and Pollock, J.S. (2007) Novel nitric oxide synthase--dependent mechanism of vasorelaxation in small arteries from hypertensive rats. Hypertension, 49, 893–901.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
About this article
Cite this article
Kang, KT. Endothelium-derived Relaxing Factors of Small Resistance Arteries in Hypertension. Toxicol Res. 30, 141–148 (2014). https://doi.org/10.5487/TR.2014.30.3.141
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.5487/TR.2014.30.3.141