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(Circulation Research. 2001;89:114.)
© 2001 American Heart Association, Inc.

Reports

Redox Signaling of the Arteriolar Myogenic Response

P. T. Nowicki, S. Flavahan, H. Hassanain, S. Mitra, S. Holland, P. J. Goldschmidt-Clermont, N. A. Flavahan

From the Heart and Lung Research Institute (P.T.N., S.F., H.H., S.M., N.A.F.), Ohio State University, Columbus, Ohio; National Institute of Allergy and Infectious Diseases (S.H.), Bethesda, Md; and Duke University (P.J.G.-C.), Durham, NC.

Correspondence to N.A. Flavahan, PhD, Heart and Lung Research Institute, 473 West 12th Ave, Room 110E, Columbus, OH 43210. E-mail flavahan-1{at}medctr.osu.edu

Abstract

Arteriolar vascular smooth muscle cells (VSMCs) are mechanosensitive, constricting to elevations in transmural pressure (P_TM). The goal of the present study was to determine using mouse isolated tail arterioles and arteries whether oxidant signaling regulates this myogenic response. In response to P_TM elevation, VSMCs of arterioles but not arteries generated constriction and increased reactive oxygen species (ROS) activity (using the H₂O₂-sensitive probe dichlorodihydrofluorescein). Arterioles had increased expression of NADPH oxidase components compared with arteries. Inhibition of NADPH oxidase, using mice with targeted impairment of enzyme components (p47^phox or rac1) or diphenyleneiodonium, prevented the pressure-induced generation of ROS. When ROS activity was inhibited, either by inhibiting NADPH oxidase or with N-acetylcysteine, the myogenic constriction was abolished. The myogenic constriction was also inhibited by catalase, which inactivates H₂O₂, but was unaffected by a cell-permeant mimic of superoxide dismutase (MnTMPyP). ₁-Adrenergic constriction was not associated with altered ROS activity and was not affected by inhibition of NADPH oxidase or ROS. Exogenous H₂O₂ constricted VSMCs of arterioles but not arteries. Thus, NADPH oxidase and ROS, in particular H₂O₂, contribute to the myogenic response of arteriolar VSMCs.

Key Words: H₂O₂ • smooth muscle • pressure

Vascular smooth muscle cells (VSMCs) of arterioles, but not arteries, are mechanosensitive, constricting to elevations in transmural pressure (P_TM). This myogenic response contributes to blood flow autoregulation and the establishment of basal vascular tone.¹ The response is an inherent property of arteriolar VSMCs involving calcium-dependent actin/myosin interaction, but the more proximal signaling components have not been clearly defined.¹ In cultured cells, mechanical stress initiates integrin-dependent activation of rho GTPases (rho, rac1, and CDC42), leading to reorganization of the cytoskeleton.^2,3 Cytoskeleton reorganization by rac1 is mediated by NADPH oxidase and generation of reactive oxygen species (ROS).⁴ This enzyme complex, comprising Nox1, p47^phox, p67^phox, p22^phox, and rac1, is a key signaling system in cultured, noncontractile VSMCs.^5,6 The aim of the present study was to determine whether the rac1/NADPH oxidase/ROS signaling pathway regulates the myogenic response of arteriolar VSMCs.

Materials and Methods

Vasomotor Responses
Mouse-tail arterioles and arteries were cannulated in a microperfusion chamber (Living Systems) and studied in the absence of flow as described.⁷ Unless stated otherwise, arterioles with intact endothelium were analyzed. Involvement of animals in the study was approved by the Ohio State University Animal Care and Use Committee.

ROS Determination
Endothelium-denuded vessels⁷ were incubated with the H₂O₂-sensitive probe 5-(and 6)-chloromethyl-2',7'-dichlorodihydro-fluorescein diacetate (DCF), 5 µg/mL, for 30 minutes (37°C, P_TM of 10 mm Hg). Because activation of DCF fluorescence is irreversible, fluorescent images (Zeiss, LSM 410) were captured at a P_TM of 10 mm Hg before and after P_TM had been increased (90 mm Hg, 1 minute). Maintaining vessels at 10 mm Hg did not change DCF fluorescence. Images were quantified using Metamorph software.

Mice
Transgenic mice expressing a dominant-negative mutant of human rac1 (rac-DN, cDNA; gift of Alan Hall, London, England), with threonine17 to asparagine substitution, were generated in FVB/N mice using the smooth muscle -actin promoter (gift of Art Strauch, Ohio State University, Columbus, Ohio). The genome of the mice incorporated the cDNA of rac-DN, including its polyadenylation site. Founder mice were selected on the basis of Southern blot analysis, and one confirmed to have the highest number of human rac-DN gene copies used to establish a stable transgenic line by breeding it with nontransgenic FVB/N mates. Reverse transcriptase–polymerase chain reaction analysis confirmed expression of rac-DN in smooth muscle, including blood vessels and intestine, whereas the transcript was not detected in control mice nor in the brain, heart, liver, skeletal muscle, and testis of transgenic mice. Responses in rac-DN mice were compared with nontransgenic littermates. All other experiments were performed on C57Bl6 mice; p47^phox-/- mice⁸ were congenic to C57Bl6.

Western Blot Analysis
Endothelium-denuded vessels from 20 mice were processed as described.⁷ Antibodies were ß-actin (Sigma), p47^phox, p67^phox (Transduction Laboratories), and rac-1 (Upstate Biotechnology).

Data Analysis
Data are expressed as mean±SEM for n number of animals. Vasomotor responses were expressed as percentage change in the basal diameter at 10 mm Hg. Statistical evaluation was by Student’s t test, except for multiple comparisons, when ANOVA followed by Scheffe’s analysis was used.

Results

At a P_TM of 10 mm Hg, the internal diameters of arterioles and arteries were 88.5±5.4 µm (n=18) and 184.4±13.4 µm, respectively (n=8). An increase in P_TM (10 to 90 mm Hg) caused arterioles to dilate, then constrict and initiate vasomotion, maintaining a diameter similar to that at a P_TM of 10 mm Hg (Figure 1A). The dilation represented passive opening and was dramatically increased by vasodilators (Figure 1A). Increasing P_TM in arteries caused only passive dilation, and vasodilators had no effect (Figure 1A).

View larger version (29K): [in this window] [in a new window]   Figure 1. A, Increased PTM (10 to 90 mm Hg, •) caused dilatation (upward movement) and then constriction of arterioles. Vasodilators (papaverine 100 µmol/L plus nitroprusside 10 µmol/L) abolished the myogenic response. In arteries, elevated PTM caused passive dilation that was unaffected by vasodilators. B, Increased PTM (10 to 90 mm Hg) increased ROS activity in arteriolar VSMCs, assessed by LSM analysis of DCF fluorescence. Inhibition of ROS (catalase 3000 U/mL) or impaired activity of NADPH oxidase (DPI 1 µmol/L; p47phox-/- or rac-DN arterioles) reduced basal ROS activity and prevented the increase to elevated PTM. Arteries had reduced ROS activity, which did not increase after PTM elevation. Bar=50 µm.

Elevating P_TM in arterioles increased ROS activity in VSMCs (2.53±0.30-fold increase in DCF fluorescence, n=13) (Figure 1B). The basal level of ROS was reduced and the pressure-induced elevation was abolished by the antioxidant N-acetylcysteine (NAC) (20 mmol/L, data not shown) or by impairment of NADPH oxidase using arterioles from p47^phox-/- or rac-DN mice or using the nonselective inhibitor diphenyleneiodonium (DPI) (1 µmol/L) (Figure 1B). In contrast, arteries had low levels of ROS activity, which did not increase after P_TM elevation (Figure 1B). Arteries had decreased expression of the NADPH oxidase components rac1, p47^phox, and p67^phox compared with arterioles (Figure 2D).

View larger version (28K): [in this window] [in a new window]   Figure 2. NADPH oxidase and myogenic responses. A and B, Myogenic response to PTM elevation (10 to 90 mm Hg, •) was reduced by DPI and in arterioles from p47phox-/- or rac-DN mice. Traces (A) and mean data (±SEM, for n=3 to 13) (B) are presented. C, Impaired activity of NADPH oxidase (DPI; p47phox-/- and rac-DN mice) did not affect constriction to the 1-adrenergic agonist phenylephrine (n=3 to 4). D, Immunoblots demonstrate increased expression of rac1, p67phox, and p47phox in arterioles compared with arteries (representative of 4 experiments). E, Inhibition of NO synthase with L-NAME (10-4 mol/L) did not affect the response of control or p47phox-/- arterioles to PTM elevation (10 to 90 mm Hg, •) (representative of 4 experiments).

The myogenic constriction to elevated P_TM was inhibited by impairment of NADPH oxidase (rac-DN or p47^phox-/- arterioles; DPI, 1 µmol/L), and only passive dilation was observed (Figures 2A and 2B). Similar results were obtained by inhibiting ROS with NAC (20 mmol/L) (Figures 3A and 3B). Inhibition of NADPH oxidase and decreased ROS activity, in particular superoxide, might depress constriction indirectly by augmenting endothelium-derived nitric oxide (NO).⁹ However, inhibition of NADPH oxidase (DPI; p47^phox-/- or rac-DN arterioles) or ROS activity (NAC) also inhibited the myogenic response in endothelium-denuded arterioles or in the presence of N^G-nitro-L-arginine methyl ester (L-NAME) (100 µmol/L), an NO synthase inhibitor (Figure 2E and data not shown). Furthermore, the myogenic constrictor response was not affected by a cell-permeant mimic of superoxide dismutase (SOD), MnTMPyP,⁴ which catalyzes the dismutation of superoxide to H₂O₂, but was abolished by catalase, which inactivates H₂O₂ (Figures 3A and 3B). The inhibitory effect of catalase on myogenic constriction and DCF fluorescence (Figures 1B, 3A, and 3B) was maximal after 4 hours, consistent with intracellular accumulation in VSMCs.¹⁰ Exogenous H₂O₂ constricted endothelium-denuded arterioles but not arteries (Figure 3D).

View larger version (28K): [in this window] [in a new window]   Figure 3. ROS and myogenic responses. A and B, Myogenic response to elevation in PTM (10 to 90 mm Hg, •) was not affected by the SOD mimic MnTMPyP (25 µmol/L, SODm) but was abolished by NAC (20 mmol/L) or catalase (3000 U/mL). Traces (A) and mean data (±SEM, for n=3 to 5) (B) are presented. C, Constriction to phenylephrine was not altered by NAC or catalase (n=3 to 5). D, Exogenous H2O2 (10 µmol/L) constricted endothelium-denuded arterioles but not arteries (representative of 5 experiments).

Constriction to the ₁-adrenergic agonist phenylephrine was not associated with increased ROS activity (data not shown) and was not affected by inhibition of NADPH oxidase (DPI; rac-DN or p47^phox-/- arterioles) or of ROS (NAC, catalase) (Figures 2C and 3C).

Discussion

Elevation in P_TM increased ROS activity in arteriolar VSMCs. The source of ROS was likely to be NADPH oxidase based on the reduced activity in p47^phox-/- or rac-DN arterioles and the inhibitory effect of DPI. When the increase in ROS was inhibited, either by the antioxidant NAC or by inhibition of NADPH oxidase, the myogenic constriction to elevated P_TM was abolished. Therefore, oxidant signaling by the rac/NADPH oxidase/ROS pathway is essential for the myogenic response of arterioles. Because ₁-adrenergic constriction was not associated with nor affected by changes in ROS activity, the role of this pathway may be restricted to mechanotransduction and myogenic constriction.

In cultured, noncontractile VSMCs, oxidant regulation of cell growth is mediated by H₂O₂.^10,11 H₂O₂ also seems to be the predominant species involved in myogenic constriction, because (1) the myogenic response was associated with increased activity of H₂O₂, as detected by DCF; (2) the responses were inhibited by catalase but unaffected by a SOD mimic; and (3) exogenous H₂O₂ was a potent constrictor of arteriolar VSMCs. Studies in large arteries have suggested that oxidant signaling is associated predominantly with diseased phenotypes of VSMCs,^10–12 compatible with oxidant regulation of VSMC growth.^10,11 Our observations on small arteries are consistent with this proposal and suggest that under physiological conditions, oxidant signaling may be more important in arteriolar compared with arterial VSMCs.

Mouse-tail arterioles represent a novel model of the microcirculation. They demonstrated robust myogenic responses and remarkable spontaneous vasomotion, suggesting that they are a useful and somewhat unique model of the terminal arteriolar vasculature. Several mechanisms have been proposed for the arteriolar myogenic response,¹ and there is heterogeneous regulation between different vascular beds.¹³ The applicability of the present results to other vascular beds is not known. Indeed, although H₂O₂ can cause constriction through multiple mechanisms,¹⁴ it can also act as a vasodilator.¹⁵ This suggests that ROS contribution to myogenic constriction may not be universal or indicates a complex regulation of vasomotor responses by ROS.

In conclusion, elevation in P_TM causes an NADPH oxidase–dependent generation of ROS in VSMCs of tail arterioles, and these ROS, in particular H₂O₂, initiate myogenic constriction. Proximal arteries do not participate in this response because of decreased expression of NADPH oxidase, reduced production of H₂O₂, and decreased ability to constrict to H₂O₂. Altered regulation of this mechanism may contribute to heightened constriction and oxidant stress in hypertension.⁵

Acknowledgments

This work was supported by grants from the Scleroderma Research Foundation and National Institutes of Health (AR46126, HL67331, and HL56091) to N.A.F.

Received February 16, 2001; accepted June 12, 2001.

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This Article Abstract Full Text (PDF) All Versions of this Article: 89/2/114    most recent hh1401.094367v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nowicki, P. T. Articles by Flavahan, N. A. Search for Related Content PubMed PubMed Citation Articles by Nowicki, P. T. Articles by Flavahan, N. A. Related Collections Cell signalling/signal transduction Oxidant stress