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REVIEW: Overproduction of Nitric Oxide in Pathophysiology of Blood Vessels

J.-C. Stoclet*, B. Muller, R. Andriantsitohaina, and A. Kleschyov

Laboratoire de Pharmacologie et Physiopathologie Cellulaires, URA CNRS 600, Université Louis Pasteur de Strasbourg, 74, route du Rhin, BP 24, 67401 ILLKIRCH, France; fax: (33) (0) 3-88-66-46-33

* To whom correspondence should be addressed.

Received September 5, 1997
Sustained production of large amounts of nitric oxide (NO) is induced in blood vessels by inflammatory stimuli as a result of the expression of the inducible form of NO-synthase (NOS-2). This happens in systemic inflammatory reactions like septic shock and in local reactions produced by endothelium denudation and atherosclerosis. NOS-2 activity in blood vessels may protect tissues by virtue of the vasodilating, anti-thrombotic and leukocyte adhesion inhibitory effects of NO. It may also participate in vascular remodeling as a result of the antiproliferative and pro-apoptotic actions of NO. However excessive production of NO in blood vessels is involved in circulatory failure that takes place in systemic inflammatory reactions and it may be cytotoxic for surrounding tissues. For these reasons, inhibition of NO overproduction has been proposed in the treatment of septic shock. Selective inhibitors of NOS-2 activity or NO trapping agent, or both, might prove to be valuable drugs in the treatment of some inflammatory diseases. The conditions in which NO shifts from a tissue protective to a damaging role are not well elucidated. Recent findings suggest that the interactions with superoxide radicals, thiols, and metals (particularly with Fe2+) may be important not only in buffering excess NO produced by NOS-2, but also in channeling it from physiologically to pathophysiologically relevant targets. It has also been found recently that adventitial cells may play an important part in vascular NO production and generation of NO stores in the media layer. The ultimate effect of NO in blood vessels might depend on its site of production, local concentration, and interactions with other tissue components.
KEY WORDS: nitric oxide, inducible nitric oxide synthase, inflammation, nitric oxide synthase inhibitors, nitric oxide stores, dinitrosyl--iron complexes, endothelium, media layer, vascular smooth muscle, adventitia, septic shock, restenosis, atherosclerosis

It is now well established that inflammatory stimuli can induce the synthesis and the activity of the "macrophage type" or "inducible" nitric oxide synthase (NOS-2) in many eukaryotic cells, including human and animal vascular endothelial and smooth muscle cells (VSMCs) (for reviews see [1, 2]). This may result in production of large amounts of NO, far beyond the physiological levels of NO produced by the "constitutive" endothelial (NOS-3) and neuronal (NOS-1) enzymes [3].

Septic shock is the most dramatic manifestation of systemic acute inflammatory reactions in which NOS-2 is induced in blood vessels [4-6]. Local induction of NOS-2 is also associated with vascular damages such as endothelium denudation [7] and atherosclerosis [8]. However the role of the different vascular cells in the induction of NOS-2 and NO overproduction is still not clear. At high concentrations, NO probably interacts with other molecular targets in addition to those reached at low physiological concentrations [2, 3, 9, 10], resulting in damages to tissues. The conditions in which the role of NO shifts from vascular protective properties (vasodilatation, inhibition of platelet adhesion and aggregation and of leukocyte adhesion) to toxic ones may depend not only on NO tissue concentration, but also on local concentration of thiols, transition metals, and probably other compounds reacting with NO.

The aim of this short review is to summarize the findings from our and other laboratories on the pathophysiological implications of the induction of NOS-2 in blood vessels. The therapeutic potential of manipulating vascular NO will also be considered.


The first evidence that endotoxin could induce extra-endothelial production of NO arose from experiments performed in rat aortic rings, removed from rats treated with bacterial lipopolysaccharide (LPS) [11] or exposed to LPS in vitro [12, 13]. In both conditions, hyporeactivity to the vasoconstrictor effect of noradrenaline and the associated increase in guanosine 3´,5´-cyclic-monophosphate (cGMP) that occurred several hours after LPS administration were reversed by the NOS inhibitor Nomega-monomethyl-L-arginine (L-NMMA), independently from the presence or the absence of endothelium. Similar results were obtained with NO antagonists (i.e., a NO scavenger--hemoglobin, and inhibitors of NO biological activity--methylene blue and LY83583) in the rat aorta exposed to LPS [14-16] or to the inflammatory cytokine interleukin-1 (IL-1) [16], which also causes delayed vascular hyporeactivity [17].

It was soon confirmed that exposure to LPS induces the activity of an extra-endothelial NOS after a lag time of several hours in the rat aorta [18, 19], in VSMCs isolated from this tissue [20], and in endothelial cells [21]. Simultaneously, it was also reported that IL-1 and tumor necrosis factor alpha (TNF-alpha), secreted by macrophages in response to LPS, also induce NOS activity in VSMCs [22]. In all these experiments, the enzyme was identified as the inducible type because it was not activated by Ca2+ and because its induction was inhibited by both dexamethasone and cycloheximide.

There is now overwhelming evidence that the synthesis and activity of NOS-2 can be induced by inflammatory stimuli in many cells [2, 6]. In blood vessels and in VSMCs, this induction can be caused not only by exposure to LPS from gram-negative bacteria as described above [5], but also by exposure to cell wall composites of gram-positive bacteria [23-27]. As a result, VSMCs release NO or a NO-like relaxing factor [27]. Induction of NOS-2 has been reported not only in animal models of endotoxemia [6, 27, 28], but also in human arteries exposed to LPS [25, 29, 30], in patients with sepsis [4, 31-33], and in patients receiving interleukin-2 (IL-2) therapy [34]. It occurs not only in conduit arteries, as mentioned above, but also in resistance arteries [35-38] and in veins from endotoxemic animals [39]. This suggests that NO overproduction may be involved not only in the drop of peripheral resistance but also in vein dilatation observed in sepsis. However, despite the induction of NOS-2, resistance arteries from rats are not hyporeactive to noradrenaline unless exogenous L-arginine is added [35-37], and hyporeactivity of human veins exposed to LPS or IL-1 in vitro is not dependent on NOS activity [29].

Incubation with LPS alone in some cases [16] or with IL-1 or TNF-alpha, alone or associated with interferon-gamma (IFN-gamma), induces transient NOS-2 activity in cultured VSMCs. Sequential exposure to cytokines may be necessary to obtain expression of NOS-2, depending on the cell type and its differentiation. Sustained expression of NOS-2 could be observed for at least 10 days in rat aortic in organ culture exposed to LPS [40]. It is beyond the scope of this review to discuss the mechanisms of the induction of NOS at the transcriptional level [41].


The current evidence reviewed above supports the view that overproduction of NO in arteries is involved in the dramatic decrease in vascular resistance and refractory hypotension which may lead to vascular collapse in human septic shock [4]. In these patients, blood pressure and vascular resistance can be restored by administration of L-NMMA [42, 43] or methylene blue [44]. For this reason, the use of L-NMMA in the treatment of the ultimate phase of septic shock has been proposed, despite the fact that L-NMMA inhibits not only NOS-2, but also NOS-1 and NOS-3. In animals, L-NMMA and other inhibitors of NOS are able to restore blood pressure not only after NOS-2 induction, but also during the first phase of hypotension caused by LPS or IL-1 administration [11, 45-47]. This phase precedes the induction of NOS activity [48-50]. Thus, the effect of L-NMMA on blood pressure in endotoxemic animals may result, at least in part, from inhibition of NO production by the constitutive neuronal NOS-1 or endothelial NOS-3, especially the latter.

In mice, eradication of the NOS-2 gene results in decreased acute inflammatory responses and enhanced resistance to LPS-induced mortality [51]. Conversely, increased LPS-induced mortality was reported when a NOS inhibitor was administered in mice before LPS [52, 53]. The inhibitors which were used in these studies were non-selective for all the isoforms of NOS. By inhibiting endothelial NOS-3 activity, these drugs can cause excessive vasoconstriction, thrombosis and a variety of tissue damages [54-56]. Aminoguanidine which seems less potent in inhibiting the constitutive than the inducible NOS in some tissues [57], attenuates the circulatory failure and mortality in rodents injected with LPS [58]. However it seems also able to inhibit the constitutive NOS in the microvasculature in vivo [59], and to promote leukocyte adherence and reduced arteriolar diameter [60]. Recently, more potent NOS inhibitors were found in a series of S-substituted isothioureas [61]. Despite their limited selectivity on the three human recombinant NOS [61], these drugs have been described as selectively inhibiting NOS-2 activity in rodents in vivo and protecting the animals against mortality and the multiple organ dysfunction syndrome caused by LPS without producing hypertension [62, 63]. This may be due to their rearrangement to mercaptoalkyl guanidines, which inhibit selectively both NOS-2 and cyclooxygenases [64]. NG-Iminoethyl-L-lysine [65] and 2-amino-4-methylpyridine [66] were recently described as potent and selective inhibitors of NOS-2, both in vitro and in vivo. Recently, another means of manipulating NO has been proposed using iron chelates [67]. These complexes either bind NO or catalyze its degradation, and they decrease mortality in experimental septic shock.

Altogether, animal studies suggest that it could be useful to inhibit selectively NOS-2 without inhibiting NOS-1 and NOS-3. They support the view that the induction of NOS-2 had detrimental consequences in the used experimental conditions (i.e., administration of very high doses of LPS, probably not compatible with survival). However, in less extreme conditions, NO overproduction resulting from the induction of NOS-2 activity might produce beneficial tissue protective effects: vasodilatation may enhance tissue perfusion, inhibition of platelet adhesion and aggregation may produce anti-thrombotic effects, and inhibition of leukocyte-endothelial cell adhesion may prevent a crucial step in inflammatory reactions [68]. Inhibition of these effects of NO might be detrimental, especially during the early phase of the induction of the inflammatory reaction. However it might be beneficial to inhibit selectively NOS-2 in order to counteract the circulatory failure [42-44] and tissue damages once NO production becomes excessive.

The same questions as above regarding the potential therapeutic utility of selective NOS-2 inhibition can be raised in the case of other systemic inflammatory reactions than septic shock in which NOS-2 is also induced. This is the case of allograft rejection [69], IL-2 therapy [34], and the hyperdynamic state of cirrhosis, where elevated concentrations of circulating endotoxin may trigger NOS-2 induction (for reviews, see [4, 70]). NOS-2 inhibitors could also be useful in the treatment of other inflammatory diseases, and in other forms of shock (including anaphylactic and hemorrhagic) which may be associated with increased synthesis of NO [4, 70].


Induction of NOS-2 by inflammatory stimuli has been discovered in murine macrophages [71, 72]. Large quantities of NO produced by these cells are cytotoxic not only for bacteria, parasites, or tumor cells, but also for surrounding tissues. Although generally difficult, the induction of NOS-2 and production of cytotoxic NO has recently been reported in human monocytes/macrophages [73].

Immune complex-induced vascular injury in rat lungs and dermal vasculature have been found to depend on the release of excess NO [74]. Inhibition of mitochondrial respiration in vascular smooth muscle cells in culture [75] and endothelium damage [76] caused by NO overproduction have also been reported.

Cytotoxic properties of sustained high NO concentration probably result from a combination of various effects (for reviews, see [3, 9]). It has been proposed that at least some of these deleterious effects may be produced via interaction of NO with O2, leading to generation of peroxynitrite (ONOO-) and eventually its breakdown cytotoxic product OH· [77]. Under normal conditions, ONOO- formation is probably low, because endogenous superoxide dismutase removes O2. However, during inflammatory events, activated leukocytes and other cells may produce large amounts of O2. The coupled production of NO and O2 may lead to the formation of ONOO-. This compound is a toxic oxidant able to inhibit aconitase and cellular respiration [78, 79] and to cause DNA strand breaks [80]. Despite the existence of powerful detoxification mechanisms in tissues, including interactions of ONOO- with thiols and alcohol functional groups [81, 82], ONOO- activates poly-(ADP-ribose)-synthase and causes depletion in adenine dinucleotide (NAD+) and ATP [83]. It has recently been reported that this mechanism accounts for depression of mitochondrial respiration in vascular smooth muscle cells in culture exposed to LPS and IFN-gamma [84], and for depression of contractility produced by exogenous ONOO- in rat thoracic aorta [84] and pulmonary artery [85]. Thus production of endogenous ONOO- may be involved not only in cytotoxic effects but also in vascular failure caused by LPS.


Endothelial denudation accomplished by balloon withdrawal evokes adhesion and degranulation of platelets followed by proliferation and migration of medial smooth muscle cells to the intima. Although experimental balloon injury is generally performed in conditions which are not identical to those of balloon angioplasty used for the treatment of occlusive atherosclerotic coronary artery disease, restenosis after angioplasty is secondary to proliferation of vascular smooth muscle cells. Balloon injury causes the induction of NOS-2 activity in vascular smooth muscle cells [86, 87]. This may be important in the maintenance of non-thrombogenicity and prevention of vasospasm in the injured vessel. As NO decreases migration and proliferation of vascular smooth muscle cells [88, 89], the induction of NOS-2 may also be a negative feedback mechanism against proliferation. Indeed, transfection with NOS inhibits neo-intimal formation after balloon injury [90]. It has therefore been suggested that NO might play a protective role against restenosis after angioplasty. This could be a favorable case for local gene therapy.

Local induction of NOS-2 activity in non-endothelial cells has been suggested in aortas from cholesterol-fed rabbits [8]. It is possible that NO produced by NOS-2 within the atherosclerotic plaque inhibits pro-atherogenic events such as monocyte adhesion and counteracts deleterious effects of defective endothelial NO production associated with the initiation of atherosclerosis (for review, see [91]). Conversely substantial evidence indicates that oxygen free radicals are also produced in the atherosclerotic plaque, leading to the generation of ONOO-, which may contribute to tissue injury [92, 93]. It has been recently reported that hypercholesterolemia decreases tissue glutathione content, thereby impairing a detoxification mechanism against ONOO- [94]. However, oxidized low density lipoproteins are able to inhibit NOS-2 activity in macrophages [95]. This mechanism might reduce NO production by foam cells in atherosclerotic lesions. Thus, whether NO production by NOS-2 has a protective or a deleterious role (or both, depending on other factors) in atherosclerosis remains to be clarified.

NO produced by NOS-2 can cause apoptosis not only in macrophages [96] but also in VSMCs [97], as in many other cells. Recent studies suggest that apoptosis occurs in human vessels during atherosclerosis and restenosis after angioplasty [98-100]. It has recently been proposed that the regulation of cell death by apoptosis may be an important determinant of long term changes in vessel structure, and that the opposite effects of NO and angiotensin II on apoptosis may determine the cell population in blood vessels by vascular smooth muscle death as well as growth [98]. However the experimental evidence supporting this view has been obtained in vitro, in cell cultures, using exogenous NO donors. The level of endogenous NO production which would cause apoptosis via an autocrine or a paracrine mechanism is unknown.

Balance between cell death by apoptosis and cell growth is probably important not only in vascular lesions, but also in long term changes in vessel structure under the influence of vasoconstrictors and vasodilators, and in hypertension. By inducing apoptosis and inhibiting proliferation of vascular smooth muscle, NO may play a major role in vascular remodeling.


As discussed above, inflammatory stimuli can induce NOS-2 activity in endothelium, in media-adventitia layer, and in vascular smooth muscle cells in culture. However, they also induce migration of leukocytes in the vascular wall. NOS-2 induced in neutrophils and macrophages may contribute to NO overproduction in vessels [101].

The presence of endothelium during incubation with LPS accelerates the onset of NO-mediated hyporeactivity to noradrenaline in the rat aorta [102]. Direct evidence that the presence of endothelium during incubation with LPS increases NO production in the media-adventitia layer was provided by electron paramagnetic resonance (EPR) spectroscopy. Furthermore, the adventitia contains a large part of NOS-2 activity in the rat aorta exposed to LPS [103]. In addition, NO released from the adventitia contributes to relaxation of medial smooth muscle cells. These findings show that the various cells contained in the three tunicae of the vessel wall can contribute to the induction of NOS-2 and to NO production. The involved cross-talk mechanisms are not elucidated.

The existence of these interactions between the various types of vascular cells may explain the above-mentioned regional differences between the effects of LPS and inflammatory cytokines in vascular beds, depending for instance on the relative proportion of the different cell types.


Generation of various NO-containing complexes and subsequent release of NO (or a NO-like biologically active compound) from these complexes may: 1) buffer high NO concentration in case of overproduction, and 2) cause sustained functional responses. The candidates for such releasable stores are high-molecular-weight S-nitrosothiols in proteins [10, 81], dinitrosyl non-heme iron complexes (DNIC) with thiol groups of proteins [104], NO adducts with Nomega-hydroxy-L-arginine [105] and ONOO- adducts with alcohol functional groups [82]. Low-molecular-weight thiols are able to displace NO from high-molecular-weight S-nitrosothiols and FeNO from DNIC in proteins. These reactions may transfer NO to guanylyl cyclase or other targets.

The existence of release from NO stores in blood vessels might explain enhanced cGMP level or vasorelaxation independent from current NOS-2 activity (i.e., in the presence of a NOS inhibitor), but caused by an NO-like mechanism (i.e., inhibited by a NO inhibitor), reported in human vascular smooth muscle cells exposed to IL-1 [106] and in the aorta of rats treated with LPS [107].

The formation of high-molecular-weight DNIC was found in cultured endothelial cells stimulated with bradykinin or calcium ionophore [108] and in the rat aorta exposed to LPS [109]. In the latter case, these complexes were generated mainly in the media layer, from NO produced in the media and the adventitia [110]. In addition, N-acetyl-cysteine produced vasorelaxation in DNIC containing aorta, indicating that it displaced NO from stores (DNIC or other complexes) to a vasorelaxing compound [104, 109]. Low-molecular-weight DNIC is able to activate guanylyl cyclase directly and to cause vasorelaxation [104]. In addition, because of antioxidant properties of DNIC [111], its generation might represent a mechanism for vascular protection.


The induction of NOS-2 is only a part of local and systemic inflammatory responses, which include the induction of cyclooxygenase, increased production of O2 and many other events. It was beyond the scope of this brief review to discuss all these events in a comprehensive fashion, although they are obviously very important not only to understand the mechanisms of vascular inflammatory responses, but also to analyze the contribution of NO. NOS-2 induction is a highly regulated phenomenon, inhibited by some growth factors and some cytokines and modulated by several signalling mechanisms within cells (especially cyclic nucleotides). Both in local and systemic inflammatory responses, NO produced by NOS-2 may provide protective or deleterious effects. Furthermore, it may be involved in long term modulation of the vessel structure (remodeling). Recent findings support the view that the effects of NO are governed not only by its level, but also by its site of production, by diffusion in the vascular wall, generation of various NO containing compounds including "storage" forms of NO, interactions with reactive oxygen species (especially O2) and probably other mediators. Elucidation of these mechanisms is necessary to understand the circumstances in which the role of NO shifts from a protective to a damaging one and to define new therapeutic strategies.


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