Editorials |
From the Hypertension & Vascular Research Division, Henry Ford Hospital, Detroit, Mich.
Correspondence to Patrick J. Pagano, E & R Building, Room 7044, Hypertension & Vascular Research Division, Henry Ford Hospital, 2799 Grand Blvd, Detroit, MI 43202. E-mail ppagano1{at}hfhs.org
Key Words: reactive oxygen species superoxide NAD(P)H oxidoreductases muscle, smooth endothelium fibroblast
| Introduction |
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Notwithstanding the importance of an endothelial isoform of this enzyme, there is substantial evidence that NAD(P)H oxidase components throughout the vascular wall are important contributors to the impairment of endothelium-dependent responses and the development of hypertension. Early studies suggested the importance of O2 in the vasculature of spontaneously hypertensive rats22 by showing that exogenous infusion of superoxide dismutase (SOD) could lower blood pressure. Beginning with the demonstration by Griendling et al19 of NAD(P)H oxidase activation by Ang II, important studies by this group showed that long-term Ang II infusion increases p22phox mRNA concomitant with elevations in blood pressure and NAD(P)H oxidase-derived O2.4 23 Some studies have suggested that this induction occurs throughout the vascular wall.10 23 Recent evidence suggests that this regulation is particularly involved in forms of hypertension in which the renin-angiotensin system is activated,24 25 whereas catecholamine-induced hypertension does not increase O2 production by this oxidase system.7 23
The finding that Ang II causes vascular smooth muscle cell
hypertrophy26 27 via activation of NAD(P)H
oxidase15 19 28 has led to several studies examining other
inducers of this response in smooth muscle cells, including
platelet-derived growth factor and thrombin.29 30
Moreover, NAD(P)H oxidases are induced in fibroblasts by a number of
factors, including tumor necrosis factor-
, interleukin-1, and
transforming growth
factor-ß1.31 32 The demonstration
that NAD(P)H oxidases are involved in mitogenic signaling
in smooth muscle cells33 34 35 and
fibroblasts36 implicated their relevance in
atherosclerosis. Moreover, several studies have shown
upregulation of O2-generating
activity in hypercholesterolemia and
atherosclerosis3 37 and the relevance of
nonendothelial
O2 sources in the impairment
of endothelium-dependent responses in this disease
state.38 p22phox expression is
increased across the vascular wall with the progression of
atherosclerosis,39 and, in fact, a
polymorphism of the p22phox gene has been
associated with coronary artery disease.40
However, Hsich et al41 recently demonstrated that knockout
of the p47phox gene does not affect the
progression of atherosclerosis. Hence, these data
support the involvement of the smooth muscle isozyme in this process,
which does not seem to require
p47phox.21 Because the study by
Hsich et al41 examined the role of
p47phox in atherosclerosis only
under normotensive conditions, it will be important to determine
whether p47phox can play a role in
atherosclerosis under hypertensive conditions in which
Ang II is elevated.
There has been very little work addressing the contribution of NAD(P)H oxidases in the various vascular segments, particularly in endothelium-dependent responses. The study by Görlach et al1 begins to delineate a specific role for the endothelial isoform of NAD(P)H oxidase in impairment of endothelium-dependent relaxation. For example, the authors demonstrate the functional involvement of gp91phox in endothelial cell NAD(P)H oxidase by comparing phorbol-12-myristate-13-acetate (PMA)stimulated oxidase activity from intact wild-type control aortas with denuded aortas and aortas from gp91phox/ mice. The study also presents very interesting data showing that gp91phox-deficient mouse aortas exhibit better endothelium-dependent relaxation than wild-type aortas. This is certainly consistent with gp91phox deficiency in the endothelium ameliorating O2 levels and preserving relaxation. In fact, in this study, gp91phox was detected in the endothelium, but not in the smooth muscle where the homologue mox1 was detected, consistent with previous reports.13 20 21 Moreover, the study by Görlach et al1 also reports that endothelial denudation completely abolished PMA-induced O2, suggesting that only the endothelial NAD(P)H oxidase source is protein kinase Cdependent, and, hence, similar to the phagocyte oxidase that includes gp91phox. In light of a recent report that thrombin can cause human aortic smooth muscle p47phox to translocate to membranes concomitant with increased O2 formation,30 a process known to be protein kinase Cdependent,42 it is not entirely clear why PMA did not activate the aortic smooth muscle in these studies. However, this could suggest a more complex signal transduction activated by thrombin.
In comparisons made on aortic segments,1 it is possible that endothelial denudation caused damage to the media or adventitia. In our own experiments using conventional means to mechanically denude the endothelium, we have observed marked reduction of the adventitia. Therefore, it is necessary that each segment be assessed carefully. Wang et al9 showed that application of NO to the adventitial side of a blood vessel causes weaker relaxation than application to the luminal side of a denuded vessel and that exogenous SOD normalizes these responses. In a subsequent study, O2 detection was greater from the adventitial versus luminal aspect of a denuded vessel, and adventitial O2 seemed to inactivate EDRF/NO, promoting the generation of passive tone in Ang IIinduced hypertension.10 These studies suggest a broad scope of interaction of endothelium-derived NO with O2. Although it is intuitive that endothelial and medial sources of O2 would impede endothelium-derived NO, it is not clear whether more distant O2 can substantially inactivate this NO source. However, a large O2 source in the outer segments of the blood vessel is likely to be relevant to bioactivity of endothelium-derived NO. Beckman and Koppenol43 describe O2 as one of three major reactants with NO that lowers its bioactive concentrations over its diffusion radius of 100 to 300 µm.44 This phenomenon is related to the ability of NO to diffuse faster than it reacts with most biological substances.44 Combined with its high rate constant of reaction with O2, it seems plausible that NO would instantaneously traverse the vessel wall to the adventitia and media and be inactivated by these substantial sources of O2, thus lowering steady-state concentrations at the endothelium-smooth muscle interface. Consistent with this hypothesis, in our recent experiments in preconstricted isolated microperfused abdominal mouse aortas where the adventitia was suffused independently, application of a nonpressor concentration of Ang II (10 pmol/L) to the adventitial compartment markedly attenuated endothelium-dependent relaxation in response to acetylcholine. This effect was completely restored by briefly applying SOD to the adventitial compartment simultaneously with application of acetylcholine to the luminal perfusate (F.E. Rey, J.L. Garvin, P.J. Pagano, 2000, unpublished data). Ongoing studies are addressing the relative roles of each cell type to endothelium-dependent responses by cell-specific targeting of NAD(P)H oxidase inhibitors.
Finally, in addition to highly differentiated smooth muscle cells that
express
-actin and myosin heavy chain, the vascular media has been
shown to contain cells that do not express these markers and may be
related to fibroblasts.45 A provocative report
by Patel et al46 shows that these nonmuscle fibroblasts
are present in very high amounts in primary cultures of the iliac
arterial media, and their number varies greatly among
vascular beds. Cultures of aortas contain lower proportions of these
cells, and cultures of coronary media contain the lowest. That
report also shows that adventitial "nonmuscle fibroblasts" have
several characteristics which could enable them to populate vascular
media and provide nidus for lesion formation.46 Thus, it
is important to carefully examine the relevance of
gp91phox in the vascular media depending on its
origin.
Although the present study by Görlach et al1 demonstrates the significant role of endothelial gp91phox-containing NAD(P)H oxidase, more than an endothelial source of gp91phox-containing NAD(P)H oxidase should be considered when evaluating the effect of this enzyme on endothelium-dependent relaxation and vascular homeostasis. Furthermore, with mounting evidence of the production of NO in various segments of the blood vessel, either under physiological or pathophysiological conditions,47 48 the various isotypes of this NAD(P)H oxidase throughout the vessel wall are likely to have a significant role.
| Footnotes |
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| References |
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-subunit cloning and expression in
rat aortic smooth muscle cells. Biochim Biophys Acta. 1995;1231:215219.[Medline]
[Order article via Infotrieve]
activates a
p22phox-based NADH oxidase in vascular smooth
muscle. Biochem J. 1998;329:653657.
.
Biochem J. 1989;263:539545.[Medline]
[Order article via Infotrieve]
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