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(Circulation Research. 2000;87:1.)
© 2000 American Heart Association, Inc.

Editorials

Vascular gp91^phox

Beyond the Endothelium

Patrick J. Pagano

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

Top Introduction References

 
In this issue of Circulation Research, Görlach et al¹ present compelling evidence for conventional gp91^phox-containing NAD(P)H oxidase in the vascular endothelium and for the functional involvement of gp91^phox 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 colleagues^{12 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 gp91^phox in vascular smooth muscle, although a homologue, mox1, has been suggested to stand in for gp91^phox.²¹ In addition, my colleagues and I have shown that the vascular adventitia contains 4 phagocyte-like components, including gp91^phox,^{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 gp91^phox (amino acids 251 to 532 of neutrophil gp91^phox) identical in sequence to rabbit leukocyte gp91^phox (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 p22^phox 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 hypertrophy^{26 27} via activation of NAD(P)H oxidase^{15 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 cells^{33 34 35} and fibroblasts³⁶ implicated their relevance in atherosclerosis. Moreover, several studies have shown upregulation of O₂^–-generating activity in hypercholesterolemia and atherosclerosis^{3 37} and the relevance of nonendothelial O₂^– sources in the impairment of endothelium-dependent responses in this disease state.³⁸ p22^phox expression is increased across the vascular wall with the progression of atherosclerosis,³⁹ and, in fact, a polymorphism of the p22^phox gene has been associated with coronary artery disease.⁴⁰ However, Hsich et al⁴¹ recently demonstrated that knockout of the p47^phox 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 p47^phox.²¹ Because the study by Hsich et al⁴¹ examined the role of p47^phox in atherosclerosis only under normotensive conditions, it will be important to determine whether p47^phox 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 gp91^phox 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 gp91^phox-deficient mouse aortas exhibit better endothelium-dependent relaxation than wild-type aortas. This is certainly consistent with gp91^phox deficiency in the endothelium ameliorating O₂^– levels and preserving relaxation. In fact, in this study, gp91^phox 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 gp91^phox. In light of a recent report that thrombin can cause human aortic smooth muscle p47^phox 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 gp91^phox in the vascular media depending on its origin.

Although the present study by Görlach et al¹ demonstrates the significant role of endothelial gp91^phox-containing NAD(P)H oxidase, more than an endothelial source of gp91^phox-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

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

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