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Symposium Reports |
1 The William Harvey Research InstituteBarts and the London, Queen MaryUniversity of London, CharterhouseSquare, London EC1M 6BQ, UKEmail: t.d.warner{at}qmul.ac.uk
Research into local mediators in the blood vessel wall has been an area of great activity ever since the 1960s, when Florey remarked that the endothelium was ‘more than a nucleated cellophane wrapper’ (Florey, 1966). In the 1970s, prostanoids, particularly prostaglandin I2 (PGI2), were the most popular research targets following the report from John Vane's group of a prostanoid which relaxed vascular smooth muscle (Moncada et al. 1976). In the 1980s, research into nitric oxide (NO) came to the fore after Furchgott and Zawadzki's report on the requirement of the endothelium for the relaxation of blood vessels in response to acetylcholine (Furchgott & Zawadzki, 1980). It subsequently became apparent, following the use of inhibitors of NO and PGI2 in experimental systems, that there were further pathways within blood vessels which mediated relaxant responses. Debate about the identity of these pathways and how they interact continues.
This issue contains papers by two speakers from the symposium entitled Short-lived Mediators in the Blood Vessel Wall, held as part of Life Sciences 2007 in Glasgow on 12th July 2007, that addressed this debate. The symposium was part of a joint meeting of the Biochemical Society, the British Pharmacological Society and The Physiological Society. Opening the symposium, Jane Mitchell (London, UK) gave an overview of the effects of NO and PGI2 within the blood vessel and their signalling. In particular, she focused upon actions of PGI2 mediated by the nuclear receptors, peroxisome proliferator-activated receptors (PPARs; Mitchell et al. 2007). David Bishop-Bailey (London, UK) reviewed the current understanding of epoxyeicosatrienoic acids (EETs; Wray & Bishop-Bailey, 2007). The EETs are produced through the metabolism of arachidonic acid by cytochrome P450 enzymes. These molecules appear to have wide-ranging effects on the vascular system, including relaxation of vascular smooth muscle and modulation of inflammatory responses; one selected oral communication from this symposium by Mairéad Carroll (New York, USA) outlined her investigation into the role of EETs in renal protection. Currently, there is little evidence regarding the endogenous receptors for EETs and the pathways responsible for their actions. David Bishop-Bailey's article in this volume (Wray & Bishop-Bailey, 2007) explores the possible role of EETs as endogenous ligands for PPARs, contributing further to the story developed by Jane Mitchell (Mitchell et al. 2007).
In addition to the speakers whose papers we see here, the symposium also saw presentations from Giuseppe Cirino (Naples, Italy) and Arthur Weston (Manchester, UK). Giuseppe Cirino presented evidence of hydrogen sulphide (H2S) as a newly discovered short-lived gaseous mediator in the blood vessel wall. Hydrogen sulphide is well known as the toxic gas that smells like rotten eggs; however, recently more attention has been paid to its activities as a messenger in both the cardiovascular and the central nervous systems. Hydrogen sulphide (H2S) is formed by two enzymes, one of which, cystathionine-
-lyase (CSE), is present in smooth muscle cells (Wang, 2002). Measurable quantities of H2S have been found in both human and rat tissues, including blood vessels, and in serum (Wang, 2002; Fiorucci et al. 2006). Evidence of its physiological role has been provided by in vitro studies, which have shown that H2S relaxes blood vessels, such as the rat aorta and portal vein (Wang, 2002), while in vivo studies show that bolus intravenous injections of H2S to rats causes transient decreases in blood pressure (Wang, 2002). Further investigation of these results in vivo using selective ion channel modulators, such as pinacidil (an ATP-sensitive potassium channel, KATP, opener) and glibenclamide (KATP channel blocker), indicate that the relaxant effects of H2S are dependent upon activation of the KATP channel on smooth muscle cells; a concept that is supported by electrophysiological studies (Fiorucci et al. 2006). There are also interesting interactions between H2S and NO within the vascular system. Nitric oxide enhances endogenous H2S production by increasing CSE activation and expression (Wang, 2002), while H2S markedly increases the relaxation of vascular tissues in response to a NO donor (Fiorucci et al. 2006). Matthew Whiteman (Exeter, UK) also gave a selected oral communication which proposed a role for H2S in the regulation of the availability of NO in the vascular system, suggesting a further interaction between these mediators. Hydrogen sulphide may also act on endothelial cells to increase the release of other vasodilating factors, contributing to its vascular effects (Wang, 2002). Future investigation into the action of H2S would benefit from the development of selective enzyme inhibitors for CSE, which would give us greater insight into this third gaseous signalling molecule, in addition to NO and carbon monoxide, and its particular roles in health and disease.
Arthur Weston provided an overview of his current opinions in the more contentious field of research into endothelium-derived hyperpolarization factor (EDHF). Endothelium-derived hyperpolarization factor was identified as a third endothelium-dependent factor responsible for the relaxations of smooth muscle that persisted after inhibition of the endogenous production of NO and PGI2. Since these relaxations were associated with a hyperpolarization of vascular smooth muscle cells, the unknown mediator was named EDHF. ‘Release’ of EDHF is initiated by an increase of intracellular calcium in endothelial cells, and the consequential activation of endothelial cell small conductance calcium-activated K+ (SKCa) and intermediate conductance calcium-activated K+ (IKCa) channels, which elicit a hyperpolarization of endothelial cells (Busse et al. 2002). Blockers of these channels, TRAM-34 (([1-(2-chlorophenyl) diphenyl) methyl]-1H-pyrazole) for IKca and apamin for SKca, prevent EDHF-induced relaxation of blood vessels and are used pharmacologically to investigate EDHF (Feletou & Vanhoutte, 2006). While many proposals have been made over the years regarding the chemical nature of EDHF, Arthur Weston focused upon two main schools of thought. Firstly, one school of thought favours the idea that gap junctions are responsible for transmitting endothelial cell hyperpolarization from endothelial cells to vascular smooth muscle cells. Gap junctions form a low-resistance electrical pathway between cells, which permits the transfer of ions and polar molecules, and so these would allow the conductance of the hyperpolarization from the endothelial cell to the smooth muscle cell. The use of gap junction blockers together with electrophysiological measurements has illustrated the importance of gap junctions in some microcirculatory beds (Busse et al. 2002). The second school of thought comprises those who favour K+ ions as EDHF (Edwards et al. 1998). Elevated intracellular calcium leads to the opening of calcium sensitive K+ channels (KCa) on endothelial cells, which leads to an accumulation of K+ in the space between endothelial cells and smooth muscle cells. This can cause an activation of the inward-rectifying potassium channel (KIR) and the Na+,K+- ATPase, which leads to smooth muscle cell hyperpolarization (Edwards & Weston, 2004). Electrophysiological techniques have shown that when these channels are blocked by a combination of ouabain and barium, EDHF responses are abolished (Busse et al. 2002). The putative mediators suggested for EDHF are not necessarily mutually exclusive. It could be that EDHF is a range of mediators and not a single factor, and the importance of each of these ‘EDHF’ mediators varies between vascular bed and degree of vascular tone. Many factors have been postulated to be EDHF, and investigation of these has led to a greater understanding of mediators acting in the vascular system.
To conclude, this symposium provided an overview of mediators in the blood vessel wall, ranging from those which have been investigated for more than 30 years, such as PGI2, to those in which our interest is only just developing, the EETs and H2S. What we have seen is that even in the established fields of research there is much more to learn about these complex systems. Further research and understanding of these mediators and their pathways will lead to a greater understanding of the cardiovascular system in health and disease, and it is hoped will provide the springboard for the development of novel therapies.
References
Edwards G, Dora KA, Gardener MJ, Garland CJ & Weston AH (1998). K+ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature 396, 269–272.[CrossRef][Medline]
Edwards G & Weston AH (2004). Potassium and potassium clouds in endothelium-dependent hyperpolarizations. Pharmacol Res 49, 535–541.[CrossRef][Medline]
Feletou M & Vanhoutte PM (2006). Endothelium-derived hyperpolarizing factor: where are we now? Arterioscler Thromb Vasc Biol 26, 1215–1225.
Fiorucci S, Distrutti E, Cirino G & Wallace JL (2006). The emerging roles of hydrogen sulfide in the gastrointestinal tract and liver. Gastroenterology 131, 259–271.[CrossRef][Medline]
Florey HW (1966). The endothelial cell. Br Med J 2, 487–490.[Medline]
Furchgott RF & Zawadzki JV (1980). The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288, 373–376.[CrossRef][Medline]
Mitchell JA, Ali F, Bailey L, Moreno L & Harrington LS (2007). Role of nitric oxide and prostacyclin as vasoactive hormones released by the endothelium. Exp Physiol 93, 141–147.[CrossRef][Medline]
Moncada S, Gryglewski R, Bunting S & Vane JR (1976). An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature 263, 663–665.[CrossRef][Medline]
Wang RUI (2002). Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J 16, 1792–1798.
Wray J & Bishop-Bailey D (2007). Epoxygenases and peroxisome proliferator-activated receptors in mammalian vascular biology. Exp Physiol 93, 148–154.[CrossRef][Medline]
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