Novel aspects of endothelium-dependent regulation of vascular tone
2006; Elsevier BV; Volume: 70; Issue: 5 Linguagem: Inglês
10.1038/sj.ki.5001680
ISSN1523-1755
AutoresInmaculada Concepción Villar, Sally‐Anne Francis, David J. Webb, Adrian J. Hobbs, Amrita Ahluwalia,
Tópico(s)Cardiovascular, Neuropeptides, and Oxidative Stress Research
ResumoThe vascular endothelium plays a crucial role in the regulation of vascular homeostasis and in preventing the initiation and progress of cardiovascular disease by controlling mechanical functions of the underlying vascular smooth muscle. Three vasodilators: nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor, produced by the endothelium, underlie this activity. These substances act in a co-ordinated interactive manner to maintain normal endothelial function and operate as support mechanisms when one pathway malfunctions. In this review, we discuss recent advances in our understanding of how gender influences the interaction of these factors resulting in the vascular protective effects seen in pre-menopausal women. We also discuss how endothelial NO synthase (NOS) can act in both a pro- and anti-inflammatory action and therefore is likely to be pivotal in the initiation and time course of an inflammatory response, particularly with respect to inflammatory cardiovascular disorders. Finally, we review recent evidence demonstrating that it is not solely NOS-derived NO that mediates many of the beneficial effects of the endothelium, in particular, nitrite acts as a store of NO released during pathological episodes associated with NOS inactivity (ischemia/hypoxia). Each of these more recent findings has emphasized new pathways involved in endothelial biology, and following further research and understanding of the significance and mechanisms of these systems, it is likely that new and improved treatments for cardiovascular disease will result. The vascular endothelium plays a crucial role in the regulation of vascular homeostasis and in preventing the initiation and progress of cardiovascular disease by controlling mechanical functions of the underlying vascular smooth muscle. Three vasodilators: nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor, produced by the endothelium, underlie this activity. These substances act in a co-ordinated interactive manner to maintain normal endothelial function and operate as support mechanisms when one pathway malfunctions. In this review, we discuss recent advances in our understanding of how gender influences the interaction of these factors resulting in the vascular protective effects seen in pre-menopausal women. We also discuss how endothelial NO synthase (NOS) can act in both a pro- and anti-inflammatory action and therefore is likely to be pivotal in the initiation and time course of an inflammatory response, particularly with respect to inflammatory cardiovascular disorders. Finally, we review recent evidence demonstrating that it is not solely NOS-derived NO that mediates many of the beneficial effects of the endothelium, in particular, nitrite acts as a store of NO released during pathological episodes associated with NOS inactivity (ischemia/hypoxia). Each of these more recent findings has emphasized new pathways involved in endothelial biology, and following further research and understanding of the significance and mechanisms of these systems, it is likely that new and improved treatments for cardiovascular disease will result. The endothelium is as a highly specialized, metabolically active organ lining the luminal side of all blood vessels that plays an integral role in the maintenance of vascular homeostasis, mediated by a number of endothelium-derived factors. The endothelium releases an array of vasoactive mediators that not only alter the tone and growth of the underlying smooth muscle but also regulate the reactivity of circulating white cells, erythrocytes, and platelets, and govern vascular permeability. Moreover, it appears that alterations in the capacity of the endothelium to release these mediators may be a major precipitating factor in many cardiovascular disease states. Of the vasodilator factors that the endothelium can release, prostacyclin (PGI2),1.Moncada S. Gryglewski R. Bunting S. Vane J.R. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation.Nature. 1976; 263: 663-665Crossref PubMed Google Scholar nitric oxide (NO),2.Furchgott R.F. Vanhoutte P.M. Endothelium-derived relaxing and contracting factors.FASEB J. 1989; 3: 2007-2018Crossref PubMed Google Scholar, 3.Ignarro L.J. Buga G.M. Wood K.S. et al.Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.Proc Natl Acad Sci USA. 1987; 84: 9265-9269Crossref PubMed Google Scholar, 4.Palmer R.M. Ferrige A.G. Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor.Nature. 1987; 327: 524-526Crossref PubMed Google Scholar and endothelium-derived hyperpolarizing factor (EDHF)5.Chen G. Suzuki H. Weston A.H. Acetylcholine releases endothelium-derived hyperpolarizing factor and EDRF from rat blood vessels.Br J Pharmacol. 1988; 95: 1165-1174Crossref PubMed Google Scholar, 6.Griffith T.M. Endothelium-dependent smooth muscle hyperpolarization: do gap junctions provide a unifying hypothesis?.Br J Pharmacol. 2004; 141: 881-903Crossref PubMed Scopus (167) Google Scholar, 7.Ahluwalia A. Hobbs A.J. Endothelium-derived C-type natriuretic peptide: more than just a hyperpolarizing factor.Trends Pharmacol Sci. 2005; 26: 162-167Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar are the most significant. PGI2 is synthesized by cyclooxygenase (COX) isozymes, of which, essentially, two have been identified. COX-1 is a constitutive enzyme expressed in the vascular endothelium and thought to contribute to the maintenance of vascular homeostasis (a splice variant of COX-1, sometimes referred to as COX-3, has also been reported8.Chandrasekharan N.V. Dai H. Roos K.L. et al.COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression.Proc Natl Acad Sci USA. 2002; 99: 13926-13931Crossref PubMed Scopus (1252) Google Scholar). COX-2 is an inducible isozyme that is thought to be expressed in the cardiovascular system (and immune cells) only during pathogenic episodes, although there is some evidence to suggest that this isoform is constitutively present in human endothelial cells.9.Grosser T. Fries S. FitzGerald G.A. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities.J Clin Invest. 2006; 116: 4-15Crossref PubMed Scopus (610) Google Scholar PGI2 elicits smooth muscle relaxation by activating specific cell-surface receptors (IP) that are G-protein-coupled to adenylyl cyclase and thereby elevate cyclic adenosine monphosphate levels.10.Mitchell J.A. Warner T.D. COX isoforms in the cardiovascular system: understanding the activities of non-steroidal anti-inflammatory drugs.Nat Rev Drug Discov. 2006; 5: 75-86Crossref PubMed Scopus (149) Google Scholar NO is synthesized from L-arginine by NO synthases (NOS) and causes vasodilatation via activation of soluble guanylyl cyclase generating cyclic guanosine monophosphate.11.Moncada S.R. Palmer M. Higgs E.A. Nitric oxide: physiology, pathophysiology, and pharmacology.Pharmacol Rev. 1991; 43: 109-142PubMed Google Scholar Under physiological conditions, two 'constitutive' forms of NOS play a role in NO production, predominantly endothelial NOS (eNOS) and to a lesser extent neuronal NOS.12.Semenza G.L. New insights into nNOS regulation of vascular homeostasis.J Clin Invest. 2005; 15: 2976-2978Crossref Scopus (15) Google Scholar A third isoform, inducible NOS (iNOS), is expressed in a number of inflammatory cell types and has an essential role in vascular inflammation.13.Hauser B. Radermacher P. Thiemermann C. Matejovic M. Nitric oxide, bacteria, and host defense in sepsis: who needs what?.Shock. 2004; 22: 588-590Crossref PubMed Scopus (11) Google Scholar The constitutive enzymes produce low-level NO, important for maintaining vascular homeostasis, whereas iNOS activity results in 'high-output' NO production and this is thought to underlie its activity in inflammation. The identity of EDHF remains uncertain, although several candidates have been proposed including K+ ions, cyclic adenosine monphosphate, cytochrome P450 2C products, H2O2, spread of electrotonic current and, most recently, C-type natriuretic peptide (CNP).7.Ahluwalia A. Hobbs A.J. Endothelium-derived C-type natriuretic peptide: more than just a hyperpolarizing factor.Trends Pharmacol Sci. 2005; 26: 162-167Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar However, it is universally accepted that EDHF release/transmission from the endothelial cell occurs following opening of endothelial SKCa and IKCa.14.Edwards G. Dora K.A. Gardener M.J. et al.K+ is an endothelium-derived hyperpolarizing factor in rat arteries.Nature. 1998; 396: 269-272Crossref PubMed Scopus (764) Google Scholar Moreover, hyperpolarization of vascular smooth muscle associated with EDHF activity, in the main, involves activation of the Na+/K+-ATPase and Kir. There is considerable evidence to support the concept that these substances not only act as vasodilators but they play a multi-faceted role in vascular homeostasis, including inhibition of mitogenesis, platelet aggregation, and the extravasation of leukocytes.7.Ahluwalia A. Hobbs A.J. Endothelium-derived C-type natriuretic peptide: more than just a hyperpolarizing factor.Trends Pharmacol Sci. 2005; 26: 162-167Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 11.Moncada S.R. Palmer M. Higgs E.A. Nitric oxide: physiology, pathophysiology, and pharmacology.Pharmacol Rev. 1991; 43: 109-142PubMed Google Scholar, 15.Kubes P. Suzuki M. Granger D.N. Nitric oxide: an endogenous modulator of leukocyte adhesion.Proc Natl Acad Sci USA. 1991; 88: 4651-4655Crossref PubMed Google Scholar, 16.Vane J.R. Botting R.M. Pharmacodynamic profile of prostacyclin.Am J Cardiol. 1995; 75: 3A-10AAbstract Full Text PDF PubMed Scopus (232) Google Scholar, 17.Selemidis S. Cocks T.M. Endothelium-dependent hyperpolarization as a remote anti-atherogenic mechanism.Trends Pharmacol Sci. 2002; 23: 213-220Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar In addition to their own distinct profile of activity, there is clear evidence that these three endothelial mediators work co-operatively in a complex but integrated manner to maintain the health of the vasculature. Most notably, it appears that each individual mediator possesses the capacity to interact with components of the synthesis/activation pathways for the other mediators and thereby manipulate their activity. These relationships have been best characterized in terms of maintenance of vascular tone and occur at two levels: first, in the physiological regulation of vessel diameter, and second, as a compensatory mechanism activated when the expression or activity of an alternate mediator is deficient. For instance, endothelial regulation of vascular tone is not uniformly consistent in terms of the contribution of the three main vasodilators, NO, PGI2, and EDHF. Although NO is the predominant endothelium-derived vasodilator in conduit arteries, as one descends the vascular tree the role of NO diminishes, whereas the influence of EDHF increases.18.Shimokawa H. Yasutake K. Fujii M. et al.The importance of the hyperpolarizing mechanism increases as the vessel size decreases in endothelium-dependent relaxations in rat mesenteric circulation.J Cardiovasc Pharmacol. 1996; 28: 703-711Crossref PubMed Scopus (417) Google Scholar In this way, the absolute vasodilator capacity of the arterial system is maintained. Studies investigating the relationship between NO and EDHF have indicated that basal NO tonically inhibits EDHF responses.19.Nishikawa Y. Stepp D.W. Chilian W.M. Nitric oxide exerts feedback inhibition on EDHF-induced coronary arteriolar dilation in vivo.Am J Physiol. 2000; 279: H459-H465PubMed Google Scholar,20.Bauersachs J. Popp R. Hecker M. et al.Nitric oxide attenuates the release of endothelium-derived hyperpolarizing factor.Circulation. 1996; 94: 3341-3347Crossref PubMed Google Scholar Indeed, in many blood vessels EDHF responses are only evident once NO production has been inhibited.19.Nishikawa Y. Stepp D.W. Chilian W.M. Nitric oxide exerts feedback inhibition on EDHF-induced coronary arteriolar dilation in vivo.Am J Physiol. 2000; 279: H459-H465PubMed Google Scholar The exact mechanisms involved in this interaction between NO and EDHF remain unknown. In a similar manner, the contribution of PGI2 (and other COX products) to endothelium-dependent relaxation is often evident only after inhibition of NOS,21.Wu Y. Huang A. Sun D. et al.Gender-specific compensation for the lack of NO in the mediation of flow-induced arteriolar dilation.Am J Physiol Heart Circ Physiol. 2001; 280: H2456-H2461PubMed Google Scholar and accordingly, this is thought to be owing to a tonic inhibitory effect of NO. There is evidence to suggest that NO can both enhance and inhibit COX activity and expression. These disparate effects of NO are likely to reflect the specific nitrogen oxide species involved and its concentration.22.Mollace V. Muscoli C. Masini E. et al.Modulation of prostaglandin biosynthesis by nitric oxide and nitric oxide donors.Pharmacol Rev. 2005; 57: 217-252Crossref PubMed Scopus (205) Google Scholar,23.Deeb R.S. Shen H. Gamss C. et al.Inducible nitric oxide synthase mediates prostaglandin H2 synthase nitration and suppresses eicosanoid production.Am J Pathol. 2006; 168: 349-362Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar There are several reports demonstrating upregulation of PGI2 or EDHF in an environment where NO production has been suppressed. For example, in gracilis muscle arterioles of male eNOS knockout (KO) mice, endothelium-dependent dilatation is maintained despite the absence of NO; this compensation was shown to be PGI2-dependent as the response was markedly attenuated by the COX inhibitor indomethacin.24.Beverelli F. Bea M.L. Puybasset L. et al.Chronic inhibition of NO synthase enhances the production of prostacyclin in coronary arteries through upregulation of the cyclooxygenase type I isoform.Fundam Clin Pharmacol. 1997; 11: 252-259Crossref PubMed Google Scholar Evidence supports the concept that this provision of PGI2 originates from the upregulation of COX enzyme expression or activity.25.Doni M.G. Whittle B.J. Palmer R.M. Moncada S. Actions of nitric oxide on the release of prostacyclin from bovine endothelial cells in culture.Eur J Pharmacol. 1988; 15: 19-25Crossref Scopus (70) Google Scholar,26.Sun D. Huang A. Smith C.J. et al.Enhanced release of prostaglandins contributes to flow-induced arteriolar dilation in eNOS knockout mice.Circ Res. 1999; 85: 288-293Crossref PubMed Google Scholar However, evidence also supports the thesis that EDHF is upregulated in eNOS KO mice.27.Scotland R.S. Chauhan S. Vallance P.J. Ahluwalia A. An endothelium-derived hyperpolarizing factor-like factor moderates myogenic constriction of mesenteric resistance arteries in the absence of endothelial nitric oxide synthase-derived nitric oxide.Hypertension. 2001; 38: 833-839Crossref PubMed Google Scholar,28.Huang A. Sun D. Smith C.J. et al.In eNOS knockout mice skeletal muscle arteriolar dilation to acetylcholine is mediated by EDHF.Am J Physiol Heart Circ Physiol. 2000; 278: H762-H768PubMed Google Scholar Our own studies have demonstrated that, whilst endothelial NO tonically antagonizes myogenic constriction in resistance arteries of wild-type (WT) mice, in eNOS KO animals rather than an exaggerated myogenic reactivity, these responses remain normal as EDHF is upregulated to replace the moderating influence of NO.27.Scotland R.S. Chauhan S. Vallance P.J. Ahluwalia A. An endothelium-derived hyperpolarizing factor-like factor moderates myogenic constriction of mesenteric resistance arteries in the absence of endothelial nitric oxide synthase-derived nitric oxide.Hypertension. 2001; 38: 833-839Crossref PubMed Google Scholar This upregulation of EDHF activity is thought to be linked to NO-mediated inhibition of EDHF.19.Nishikawa Y. Stepp D.W. Chilian W.M. Nitric oxide exerts feedback inhibition on EDHF-induced coronary arteriolar dilation in vivo.Am J Physiol. 2000; 279: H459-H465PubMed Google Scholar,20.Bauersachs J. Popp R. Hecker M. et al.Nitric oxide attenuates the release of endothelium-derived hyperpolarizing factor.Circulation. 1996; 94: 3341-3347Crossref PubMed Google Scholar Exactly how this is brought about is uncertain, but studies using NO donors in rabbit carotid and porcine coronary arteries demonstrate an NO-mediated suppression of EDHF-mediated dilatation associated with an interference with the synthesis and/or release of EDHF rather than its mechanism of action.19.Nishikawa Y. Stepp D.W. Chilian W.M. Nitric oxide exerts feedback inhibition on EDHF-induced coronary arteriolar dilation in vivo.Am J Physiol. 2000; 279: H459-H465PubMed Google Scholar,20.Bauersachs J. Popp R. Hecker M. et al.Nitric oxide attenuates the release of endothelium-derived hyperpolarizing factor.Circulation. 1996; 94: 3341-3347Crossref PubMed Google Scholar Indeed, patch-clamp recordings in vascular smooth muscle cells revealed that NO donors, which did not directly affect resting membrane potential or EDHF-induced hyperpolarization, markedly attenuated EDHF release from a donor segment.20.Bauersachs J. Popp R. Hecker M. et al.Nitric oxide attenuates the release of endothelium-derived hyperpolarizing factor.Circulation. 1996; 94: 3341-3347Crossref PubMed Google Scholar Similarly, chronic inhibition of NO synthesis causes a change in the factors mediating endothelium-dependent relaxation; several studies have demonstrated a compensatory increase of PGI2 production and upregulation of COX expression.24.Beverelli F. Bea M.L. Puybasset L. et al.Chronic inhibition of NO synthase enhances the production of prostacyclin in coronary arteries through upregulation of the cyclooxygenase type I isoform.Fundam Clin Pharmacol. 1997; 11: 252-259Crossref PubMed Google Scholar, 29.Henrion D. Dechaux E. Dowell F.J. et al.Alteration of flow-induced dilation in mesenteric resistance arteries of L-NAME treated rats and its partial association with induction of cyclooxygenase-2.Br J Pharmacol. 1997; 121: 83-90Crossref PubMed Google Scholar, 30.Puybasset L. Bea M.L. Ghaleh B. et al.Coronary and systemic hemodynamic effects of sustained inhibition of nitric oxide synthesis in conscious dogs: evidence for cross talk between nitric oxide and cyclooxygenase in coronary vessels.Circ Res. 1996; 79: 343-357Crossref PubMed Google Scholar This compensatory upregulation of PGI2 and/or EDHF following suppression of NO production is also observed in models of cardiovascular disease and in humans with cardiovascular disease.21.Wu Y. 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Here, we focus on some areas of endothelial biology that have come to the fore recently, in particular, the impact of gender on endothelial responses, the role of the endothelium in determining inflammatory iNOS expression, and evidence demonstrating alternative endothelium-dependent sources of endogenous NO. Several lines of evidence support the existence of gender differences in endothelium-dependent vasodilator responses in animals37.Huang A. Sun D. Koller A. Kaley G. Gender difference in flow-induced dilation and regulation of shear stress: role of estrogen and nitric oxide.Am J Physiol Regul Integr Comp Physiol. 1998; 275: R1571-R1577PubMed Google Scholar, 38.Kauser K. Rubanyi G.M. Gender difference in bioassayable endothelium-derived nitric oxide from isolated rat aortae.Am J Physiol Heart Circ Physiol. 1994; 267: H2311-H2317PubMed Google Scholar, 39.White R.M. Rivera C.O. Davison C.A. 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Anderson T.J. et al.The endothelium in health and disease – a target for therapeutic intervention.J Smooth Muscle Res. 2003; 39: 249-267Crossref PubMed Scopus (75) Google Scholar Indeed, in many cases, endothelial dysfunction precedes the onset of disease and therefore this phenomenon may play an important role in pathogenesis.46.Celermajer D.S. Sorensen K.E. Gooch V.M. et al.Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis.Lancet. 1992; 340: 1111-1115Abstract Full Text PDF PubMed Scopus (3219) Google Scholar, 47.Celermajer D.S. Endothelial dysfunction: does it matter? Is it reversible?.J Am Coll Cardiol. 1997; 30: 325-333Abstract Full Text Full Text PDF PubMed Scopus (489) Google Scholar, 48.Schächinger V. Britten M.B. Zeiher A.M. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease.Circulation. 2000; 101: 1899-1906Crossref PubMed Google Scholar The mechanisms involved in enhanced endothelial function in females seem (intuitively) to be linked to female sex hormones. For example, flow-mediated dilatation (FMD) of the brachial artery is increased in females compared to males, a difference temporally associated with the increase in serum estradiol concentration that occurs during the menstrual cycle. Indeed, the difference in FMD disappeared during the M phase when serum levels of both estrogen and progesterone were similar to those in male subjects.49.Hashimoto M. Akishita M. Eto M. et al.Modulation of endothelium-dependent flow-mediated dilatation of the brachial artery by sex and menstrual cycle.Circulation. 1995; 92: 3431-3435Crossref PubMed Google Scholar Similarly, vasodilator responses to bradykinin are increased mid-cycle in healthy women, when estrogen levels are at their highest.50.Chan N.N. MacAllister R.J. Colhoun H.M. et al.Changes in endothelium-dependent vasodilatation and alpha-adrenergic responses in resistance vessels during the menstrual cycle in healthy women.J Clin Endocrinol Metab. 2001; 86: 2499-2504Crossref PubMed Scopus (29) Google Scholar Further, young women with premature ovarian failure (or premature menopause) have impaired endothelial function that has been directly linked to sex steroid deficiency, as treatment of these individuals for 6 months with estradiol restored endothelial function.51.Kalantaridou S.N. Naka K.K. Papanikolaou E. et al.Impaired endothelial function in young women with premature ovarian failure: normalization with hormone therapy.J Clin Endocrinol Metab. 2004; 89: 3907-3913Crossref PubMed Scopus (95) Google Scholar Ovariectomy also creates an estrogen deficient state and in such patients endothelium-dependent vasodilatation in the forearm is also attenuated.52.Pinto S. Virdis A. Ghiadoni L. et al.Endogenous estrogen and acetylcholine-induced vasodilation in normotensive women.Hypertension. 1997; 29: 268-273Crossref PubMed Google Scholar Together, these findings provide strong support for the thesis that endogenous sex hormones, particularly estrogen, play an important role in maintaining endothelial function in healthy females. There is an immense body of evidence demonstrating the beneficial effects of estrogen on endothelial and vascular function. Studies of post-menopausal women and ovariectomized (OVX) animals52.Pinto S. Virdis A. 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Colhoun H.M. et al.Changes in endothelium-dependent vasodilatation and alpha-adrenergic responses in resistance vessels during the menstrual cycle in healthy women.J Clin Endocrinol Metab. 2001; 86: 2499-2504Crossref PubMed Scopus (29) Google Scholar, 51.Kalantaridou S.N. Naka K.K. Papanikolaou E. et al.Impaired endothelial function in young women with premature ovarian failure: normalization with hormone therapy.J Clin Endocrinol Metab. 2004; 89: 3907-3913Crossref PubMed Scopus (95) Google Scholar, 52.Pinto S. Virdis A. Ghiadoni L. et al.Endogenous estrogen and acetylcholine-induced vasodilation in normotensive women.Hypertension. 1997; 29: 268-273Crossref PubMed Google Scholar, 53.Gisclard V. Miller V.M. Vanhoutte P.M. Effect of 17 beta-estradiol on endothelium-dependent responses in the rabbit.J Pharmacol Exp Ther. 1988; 244: 19-22PubMed Google Scholar, 54.Keaney Jr, J.F. Shwaery G.T. Xu A. et al.17 Beta-estradiol preserves endothelial vasodilator function and limits low-density lipoprotein oxidation in hypercholesterolemic swine.Circulation. 1994; 89: 2251-2259Crossref PubMed Google Scholar, 55.Reis S.E. Gloth S.T. Blumenthal R.S. et al.Ethinyl estradiol acutely attenuates abnormal coronary va
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