© 2000 American Heart Association, Inc.
Editorials |
Vascular gp91phox
Beyond the Endothelium
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
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Introduction |
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 Top Introduction References |
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In this issue of Circulation Research, Görlach et al1 present compelling evidence for conventional gp91phox-containing NAD(P)H oxidase in the vascular endothelium and for the functional involvement of gp91phox in endothelial cell NAD(P)H oxidase superoxide anion (O2–) production and aberrant endothelium-dependent relaxation. Many studies have implicated reactive oxygen species in the impairment of endothelium-dependent vascular responses.2 3 4 5 6 7 8 9 10 Since their initial discovery in the vasculature and the suggestion of their importance in the modulation of endothelium-derived relaxing factor nitric oxide (EDRF/NO) bioactivity, phagocyte-like NAD(P)H oxidases have been under intense study in 3 major vascular cell types.11 12 13 14 15 16 17 18 Griendling et al19 showed the presence of angiotensin II (Ang II)–activatable NAD(P)H oxidase in rat vascular smooth muscle, and Mohazzab-H and colleagues12 14 also made seminal discoveries of endothelial and smooth muscle isotypes in bovine arteries. Because of the juxtaposition of these important sources of O2- near the sites of release and action of EDRF/NO, most interest in vascular biology has concerned components in these 2 cell types. Additional studies have demonstrated molecular evidence for most NAD(P)H oxidase components in both cell types,13 15 16 20 whereas there has been scant evidence for gp91phox in vascular smooth muscle, although a homologue, mox1, has been suggested to stand in for gp91phox.21 In addition, my colleagues and I have shown that the vascular adventitia contains 4 phagocyte-like components, including gp91phox,9 10 18 and that rabbit adventitial fibroblasts contain an NAD(P)H oxidase functionally similar to the phagocyte oxidase.18 Recently, we screened a cDNA library prepared from these fibroblasts and obtained an 843-nucleotide base-pair coding region of neutrophil gp91phox (amino acids 251 to 532 of neutrophil gp91phox) identical in sequence to rabbit leukocyte gp91phox (K.A. Gauss, P.J. Pagano, M.T. Quinn, 2000, unpublished data), confirming the presence of this NAD(P)H oxidase component in aortic adventitial fibroblasts.
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 C–dependent, 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 C–dependent,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 II–induced 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.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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K. R. Smith, L. R. Klei, and A. Barchowsky Arsenite stimulates plasma membrane NADPH oxidase in vascular endothelial cells Am J Physiol Lung Cell Mol Physiol, March 1, 2001; 280(3): L442 - L449. [Abstract] [Full Text] [PDF]
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S. S. Brar, T. P. Kennedy, A. B. Sturrock, T. P. Huecksteadt, M. T. Quinn, T. M. Murphy, P. Chitano, and J. R. Hoidal NADPH oxidase promotes NF-kappa B activation and proliferation in human airway smooth muscle Am J Physiol Lung Cell Mol Physiol, April 1, 2002; 282(4): L782 - L795. [Abstract] [Full Text] [PDF]
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