Prostanoids and reactive oxygen species: Team players in endothelium-dependent contractions

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Abstract

The endothelial cells control the tone of the underlying vascular smooth muscle by releasing vasoactive substances. Endothelium-derived relaxing factors (EDRF), in particular nitric oxide have received considerable attention, but much less is known about the ability of the endothelial cells to release endothelium-derived contracting factors (EDCF). The possible players of endothelium-dependent contractions and the underlying mechanisms leading to the release of EDCF will be discussed in the present review. EDCF is likely to consist of two components: 1) prostanoids (including endoperoxides, prostacyclin, thromboxane A2, and prostaglandin E2) and 2) reactive oxygen species. The former directly activate thromboxane/prostaglandin endoperoxide (TP) receptors of the vascular smooth muscle cells which leads to their contraction, while the latter first stimulate the cyclooxygenase in the smooth muscle with subsequent stimulation of the TP receptors by the prostanoids produced. Dysfunction in calcium handling is the leading causal factor for the exacerbated occurrence of endothelium-dependent contractions in the aorta of the spontaneously hypertensive rat (SHR). The observed increased expressions of endothelial COX-1, prostacyclin synthase, thromboxane synthase and enhanced TP receptor sensitivity are not prerequisites for, but intensify the magnitude of endothelium-dependent contractions. Selective TP receptor antagonists are effective in preventing endothelium-dependent contractions in vitro which highlights the prospective use of such drugs in correcting the imbalanced release of endothelium-derived vasoactive substances that accompany vascular disease.

Introduction

Soon after Robert Furchgott's seminal proposal that endothelial cells release endothelium-derived relaxing factor (EDRF) in response to acetylcholine (Furchgott & Zawadzki, 1980), one study unexpectedly showed that in isolated canine veins, exogenous arachidonic acid and thrombin induced an increase in tension during contractions to norepinephrine, rather than the relaxations observed in the corresponding arteries (De Mey & Vanhoutte, 1982). This demonstrated the ability of the endothelium to initiate contraction of the underlying smooth muscle. It was assumed that these endothelium-dependent increases in tension were due to diffusible substances, termed endothelium-derived contracting factors (EDCF). The endothelium-dependent contractions to arachidonic acid in canine veins were prevented by inhibitors of cyclooxygenase, which prompted the conclusion that EDCF is likely to be a product of that enzyme (Miller & Vanhoutte, 1985). This conclusion has withstood the test of time (Vanhoutte et al., 2005, Vanhoutte and Tang, 2008, Vanhoutte et al., in press). Obviously, endothelial cells can produce vasoconstrictor substances other than prostanoids, in particular the peptides angiotensin II and endothelin-1, and the non-peptidic dinucleotide uridine adenosine tetraphosphate (UP4A) (Jankowski et al., 2005). However, it is uncertain whether or not the release of these substances leads to instantaneous changes in vascular tone. The present review will focus on the role of cyclooxygenases in producing vasoconstrictor substances initiating endothelium-dependent contractions, on the cellular mechanisms leading to the release of these EDCFs, on the facilitatory role of both reduced production of EDRFs and augmented formation of reactive oxygen species [ROS], and on the prostanoid receptors which ultimately initiate the contractile response of the underlying vascular smooth muscle.

Section snippets

Occurrence of endothelium-dependent contractions

The aorta of the adult spontaneously hypertensive rats (SHR) exhibits a characteristic endothelial dysfunction, defined as an impairment of endothelium-dependent relaxations (Konishi and Su, 1983, Sim and Chua, 1985). The reduced endothelium-dependent relaxation in response to acetylcholine in the aorta of the SHR is not due to a decreased release of EDRF but rather to the concomitant release of an EDCF (Lüscher and Vanhoutte, 1986, Lüscher et al., 1987b). Indomethacin (a non-selective

EDRF and EDCF balance

EDRF (principally nitric oxide in many arteries) and EDCF exert opposing effects on the vascular smooth muscle and thus behave as acute functional antagonists. Accordingly, inhibitors of nitric oxide synthase, scavengers of nitric oxide and inhibitors of guanylyl cyclase (which interfere with the production, the transfer of nitric oxide and activation of guanylyl cyclase, respectively) augments endothelium-dependent contractions (Auch-Schwelk and Vanhoutte, 1992, Yang et al., 2004b). Similarly,

The importance of endothelial cyclooxygenase

The formation of EDCF which contributes to moment-to-moment changes in vascular tone depends on the activity of endothelial cyclooxygenase. There exist two isoforms of cyclooxygenase, namely COX-1 and COX-2. Both are heme-proteins which have an equal potency to oxidize arachidonic acid into endoperoxides, the precursor of all prostaglandins (Garavito & DeWitt, 1999). Preferential inhibitors of COX-1 (such as tenidap or valeryl salicylate) abolish endothelium-dependent contractions of the SHR

Possible candidates as EDCF

There is a marked heterogeneity in the formation of EDCFs, which depends on the stimuli, the vascular bed, the age and the specific experimental animal model being studied. Endoperoxides (Auch-Schwelk et al., 1990, Ito et al., 1991, Ge et al., 1995), prostacyclin (Rapoport and Williams, 1996, Gluais et al., 2005), thromboxane A2 (Shirahase et al., 1988, Yang et al., 2004a, Gluais et al., 2006, Gluais et al., 2007), reactive oxygen species (ROS; Katusic and Vanhoutte, 1989, Katusic et al., 1993,

The involvement of prostanoid receptors

Cyclooxygenase-derived EDCF diffuses to the underlying smooth muscle and activates prostanoid receptors (Yang et al., 2003) [Fig. 2]. Prostanoid receptors are classified into five discrete types based on their sensitivity to the naturally occurring prostanoids (prostacyclin I2, thromboxane A2, prostaglandin D2, prostaglandin E2 and prostaglandin F2α). They are termed P receptors, with a preceding letter indicating the prostanoid to which they are the most sensitive to (IP, TP, DP, EP and FP) (

The importance of endothelial calcium

An increase in the endothelial intracellular calcium concentration is required to evoke EDCF-mediated responses (Fig. 2). This calcium-dependency is illustrated functionally by the repeated observation that calcium ionophores (e.g. A23187 and cyclopiazonic acids) at concentrations which induce minimal direct activation of vascular smooth muscle, causes vigorous endothelium-dependent contractions in isolated arteries (Katusic et al., 1988, Okon et al., 2002, Yang et al., 2004a, Gluais et al.,

The importance of reactive oxygen species

The heterogeneous response to different forms of ROS in various blood vessels has made it difficult to establish a direct association, and even more so that of a causal relationship, between an increase in oxidative stress and the occurrence of endothelium-dependent contractions. Endothelium-derived ROS may be considered to be EDCF, at least in the basilar artery of the dog (Katusic and Vanhoutte, 1989, Katusic et al., 1993) and the renal artery of the rat (Gao & Lee, 2005) by initiating the

Summary

The precise sequence of events that occurs during endothelium-dependent contractions first requires an accumulation of calcium, which then leads to the preferential activation of endothelial cyclooxygenase-1 (COX-1), leading to the production of EDCF(s). EDCF(s) are likely to consist of two components: 1) prostanoids [including endoperoxides, prostacyclin, thromboxane A2, and prostaglandin E2] and 2) reactive oxygen species (Fig. 2). The former directly activate thromboxane/prostaglandin

Perspectives

Because of its direct agonism at TP receptors on platelets and vascular smooth muscle and its ability to counteract the dilator effect of nitric oxide, EDCF not only increases vascular tone, but could also conceivably act as a promoter of thrombosis, atherosclerosis and other cardiovascular events (Cayatte et al., 2000, Viles-Gonzalez et al., 2005, Worth et al., 2005, Vilahur et al., 2007). Therefore, it is desirable to suppress the release and/or action of EDCF that occurs in vascular

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      Citation Excerpt :

      Vascular endothelial cells release relaxant and contractile factors, named endothelium-derived relaxing factor (EDRF) and endothelium-derived contracting factor (EDCF) respectively, to induce endothelium-dependent relaxation (EDR) and contraction (EDC) [1].

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