0frontier!
IN OXIDANT PHYSIOLOGY!
Contribution of Oxidative Stress to Endothelial Dysfunction in Hypertension
Bruno Rodrigues Silva, Laena Pernomian and Lusiane Maria Bendhack
Journal Name: ISSN:
Article type: Received on: Accepted on:
Provisional PDF published on: Frontiers website link: Citation:
Article URL: Copyright statement:
Frontiers in Physiology
1664-042X
Mini Review Article
03 Aug 2012
05 Nov 2012
05 Nov 2012
www.frontiersin.org
Silva BR, Pernomian L and Bendhack LM(2012) Contribution of Oxidative Stress to Endothelial Dysfunction in Hypertension. Front. Physio. 3:441. doi:10.3389/fphys.2012.00441
http://www.frontiersin.org/Journal/Abstract.aspx?s=818& name=oxidant%20physiology&ART DOI=10.3389/fphys.2012.00441
(If clicking on the link doesn't work, try copying and pasting it into your browser.)
© 2012 Silva, Pernomian and Bendhack. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
This Provisional PDF corresponds to the article as it appeared upon acceptance, after rigorous peer-review. Fully formatted PDF and full text (HTML) versions will be made available soon.
Contribution of Oxidative Stress to Endothelial Dysfunction in
Hypertension
A A O *
Bruno Rodrigues Silva,1 Laena Pernomian,1 Lusiane Maria Bendhack2
1 Dept. Pharmacology, School of Medicine of Ribeirao Preto - University of Sao Paulo, 2 Dept. Physics and Chemistry, Faculty of Pharmaceutical Sciences of Ribeirao Preto - University of Sao Paulo, Ribeirao Preto, SP - Brasil.
Running Title: Vascular Oxidative Stress in Hypertension
Address for correspondence:
Lusiane Maria Bendhack Laboratorio de Farmacologia
Faculdade de Ciéncias Farmacéuticas de Ribeiráo Preto - USP Av. do Café s/n°.
14040-903 Ribeiráo Preto, SP - Brazil Phone: 55-16-36024704 e-mail: bendhack@usp.br
Abstract
Endothelial dysfunction is the hallmark of hypertension, which is a multifactorial disorder. In the cardiovascular system reactive oxygen species play a pivotal role in controlling the endothelial function and vascular tone. Physiologically, the endothelium-derived relaxing factors (EDRFs) and endothelium-derived contractile factors (EDCFs) that have functions on the vascular smooth muscle cells. The relaxation induced by the EDRFs nitric oxide (NO), prostacyclin, and the endothelium-derived hyperpolarization factor (EDHF) could be impaired in hypertension. The impaired ability of endothelial cells to release NO along with enhanced EDCFs production has been described to contribute to the endothelium dysfunction, which appears to lead to several cardiovascular diseases. The present review discusses the role of oxidative stress, vascular endothelium, and vascular tone control by EDRFs, mainly NO, and EDCFs in different models of experimental hypertension.
Key Words: Oxidative stress, endothelial dysfunction, hypertension, vascular relaxation, vascular contraction, NO availability
Hypertension is a multifactorial disorder that involves many mechanisms leading to risk factors for cardiovascular diseases. Endothelial dysfunction is defined as the imbalance between the production and bioavailability of endothelium-derived relaxing factors (EDRFs) and endothelium-derived contractile factors (EDCFs), associated with increased bioavailability of oxygen reactive species (ROS) and decreased antioxidant capacity characterized as oxidative stress. In this review we will discuss the involvement of oxidative stress and vascular endothelium as well as the importance of vascular tone control, relaxation, and contraction in hypertension.
NO is an important mediator released by endothelial cells. It is produced by NO synthases (NOS), which convert L-arginine and molecular oxygen to L-citrulline and NO, using such co-factors as tetrahydrobiopterin (BH4), flavin-adenine-dinucleotide, flavin-mononucleotide, and nicotinamide-adenine-dinucleotide-phosphate (Thomas et al., 2008). The activity of NOS is regulated by substrate, cofactor availability, and electron transfer rate. The regulating factors such as arginine (Gornik and Creager, 2004) and BH4 (Bevers et al., 2006) can be affected by ROS that can lead to dysfunctional eNOS. As summarized in the Figure 1, in pathological states involving oxidative stress such as hypertension NOS could be uncoupled (Schulz et al., 2008). L-arginine is the substrate for both enzymes, NOS and arginase (Tousoulis et al. 2002). Zhang et al. (2004) showed that the activity of arginase in the endothelial cells of coronary arterioles is increased in hypertension, which impairs the NO-mediated dilation. Similarly, as reported by Chandra et al. (2012) peroxynitrite (ONOO-) and hydrogen peroxide (H2O2) increase arginase activity/expression in the endothelial cells. This should lead to NOS uncoupling with reduced NO
production and augmented superoxide anion (O2-) production. As shown by Romero e al. (2008), increased arginase activity in diabetes contributes to vascular endothelium dysfunction by decreasing L-arginine availability to NOS.
Endothelial dysfunction culminates in impaired endothelium-dependent relaxation due to decreased vascular NO bioavailability caused by ROS consumption. The result is ONOO- formation, lower NOS protein expression, or lack of substrate or co-factor for NOS (Crimi et al., 2007). The eNOS phosphorylation state can alter its activity; i.e., Akt-dependent phosphorylation at Ser1177 (human) or Ser1179 (bovine) activates eNOS (Fulton et al, 1999), while phosphorylation at Thr495 (human) or Thr497 (bovine) decreases its activation
A A 70
(Bouloumie et al., 1997). H2O2 initially raises eNOS Ser11'9 phosphorylation and activity, in parallel with transient Akt activation (Hu et al., 2008).
In vivo measurements of NO and H2O2 in the mesenteric arteries of spontaneously hypertensive rats (SHR) revealed higher baseline NO and H2O2 concentrations than normotensive rats (Zhou et al, 2008). It is known that in resistance arteries more than in conduit vessels, EDHF is an important control of vascular tone. H2O2 has been shown to be a component of EDHF in several vascular beds (Meurer et al., 2005; Shimokawa et al., 2010; Prysyazhna et al., 2012).
Peroxynitrite can also activate eNOS by increasing basal and agonistA A 70
stimulated Ser1"9 phosphorylation, although it reduces NO bioavailability and elevates O2- production (Zou et al. 2002a). eNOS exposure to oxidants like ONOO- causes increased enzymatic uncoupling and O2- generation in diabetes, that contributes to endothelial cell oxidant stress (Zou et al. 2002b). Increased
formation of ONOO" can inhibit prostacyclin synthase (PGIS) (Wu and Liou, 2005) and impairs K+ channel activation (Guterman et al., 2005).
Increased ROS bioavailability, decreased antioxidant capacity, or both occur in many models of hypertension such as SHR (Suzuki et al., 1995), Dahl salt-sensitive (Swei et al., 1997), AngII-infused rats (Laursen et al., 1997), renal hypertensive 2K-1C (Rodrigues et al., 2008), and human hypertension (Vaziri, 2004). In endothelial cells, the ROS producers are NADPH oxidase (Rajagopalan et al., 1996), xanthine oxidase (Phan et al., 1989), uncoupled NOS (Satoh et al., 2005), cyclooxygenase (COX) (Tang et al., 2007), and mitochondria (Callera et al., 2006). The DOCA-salt model present augmented oxidative stress caused by increased NADPH oxidase activity, which accounts for enhanced O2- production (Beswick et al., 2001). In 2K-1C rats, the increased vascular O2- is secondary to a protein kinase C (PKC)-mediated activation of NADPH oxidase (Heitzer et al., 1999). However, eNOS activity is reduced by phosphorylation of the Thr495 residue in the Ca2+/CaM binding domain by PKC (Mount et al., 2007). Mimicking of Thr495 dephosphorylation results in eNOS uncoupling and O2- production rather than NO generation (Lin et al., 2003). However, whether the Thr495 eNOS phosphorylation site is more phosphorylated in hypertension or contains uncoupled eNOS remains unknown.
We have investigated the vascular mechanisms involved in the vasorelaxation induced by NO donors that present potential capacity to replenish vascular NO upon reduced NO bioavailability. Most of the studies using NO donors are performed on endothelium-denuded arteries to avoid interference of endogenously produced NO (Bonaventura et al., 2004, Pereira et al., 2011). Impaired 2K-1C rat aorta relaxation is endothelium-dependent
(Callera et al., 2004) or endothelium-independent (Bonaventura et al., 2005). Vitamin-C normalized the impaired relaxation induced by a NO donor in 2K-1C rat aorta that shows the increased ROS production in the vascular smooth muscle cells (Rodrigues et al., 2008). Interestingly, the endothelium can contribute to the vasorelaxation induced by sodium nitroprusside (SNP) via NOS activation (Bonaventura et al., 2008). The endothelium negatively modulates the vasorelaxation induced by the complex (TERPY) in the rat aorta. BH4 supplementation reverses the effect of uncoupled NOS induced by TERPY (Bonaventura et al., 2009).
The altered function of endothelial cells leads to enhanced contraction (Endemann and Schiffrin, 2004). The EDCFs released under different stimuli include ET-1(Taddei et al., 2003), some prostanoids, and ROS (Tang and Vanhoutte, 2009). ET-1 activates ETA and ETB receptors. ETA receptors are expressed on smooth muscle cells and promote contraction. ETB receptors are located on endothelial and smooth muscle cells, with opposite effects. Smooth muscle ETB activation evokes contraction, whereas endothelial ETB activation induces relaxation (Taddei et al., 2003). The imbalance in the expression of receptors or increased ET-1 production can contribute to hypertension. Hypertension associated with elevated levels of Angll leads to high vascular ET-1 production (Dohi et al., 1992) as well as ROS originated from NADPH oxidase (Touyz et al., 2002). Both factors are related to larger contractility in hypertensive rat resistance arteries.
The SHR aorta exhibits a characteristic endothelial dysfunction that is not due to decreased EDRF release, but it is the result of simultaneous EDCF release. Indomethacin, a non-selective COX inhibitor, restores the blunted
relaxation in SHR aorta to the level of normotensive (Lüscher & Vanhoutte, 1986), which suggests that this EDCF must be a product of the COX. Endothelium-dependent contraction is reported in the rat aorta, mesenteric and femoral arteries, and cerebral arterioles. It occurs in healthy animals, but EDCF release is exacerbated by hypertension. Selective COX-1 inhibitors abolish endothelium-dependent contraction in SHR aorta, while selective COX-2 inhibitors only display modest responses (Tang & Vanhoutte, 2009).
Endoperoxides, PGI2, TXA2 and ROS are proposed as COX-derived EDCFs. Increased endothelial [Ca2 ]i is required to evoke EDCF-mediated responses. Dysfunction in Ca2 handling within the endothelium is important for the exacerbation of endothelium-dependent contractions in SHR aorta (Tang et al, 2007).
Independent of the genesis of hypertension, specific ROS such as H2O2 modify the vascular activity of NOS and COX in concentration-dependent way (Cai et al., 2003; Gil-Longo et al., 2005). In hypertension, ROS are involved in augmented EDCFs and diminished EDRFs release. In the L-NAME (Qu et al., 2010) and SHR (Félétou et al., 2009) models there is increased COX-derived production of contractile prostanoids. Physiologically, PGI2 evokes vasorelaxation, whereas in aging animals or SHR it induces contraction (Vanhoutte, 2011).
Inhibitors of COX (Taddei et al., 1997), NADPH oxidase (Costa et al., 2009), and xanthine oxidase (Ellis et al., 1998) or antioxidant agents such as Vitamin-C (Nishi et al., 2010) seem to diminish ROS production, and EDCFs generation.
In conclusion, the data presented in this work suggest that decreased NO availability along with enhanced EDCFs production contribute to the endothelium dysfunction and impaired vascular relaxation in hypertension (Fig. 1). Considering the enormous progress in the area in the last years, this work addresses the function of oxidative stress on the pathogenesis of hypertension.
References
Beswick, R.A., Dorrance, A.M. and Romulo, R.C.L. (2001). NADH/NADPH oxidase and enhanced superoxide production in the mineralocorticoid hypertensive rat. Hypertension 38, 1107-1111.
Bevers, L.M., Braam, B., Post, J.A., van Zonneveld, A.J., Rabelink, T.J., Koomans, H.A., Verhaar, M.C. and Joles, J.A. (2006). Tetrahydrobiopterin, but not L-arginine, decreases NO synthase uncoupling in cells expressing high levels of endothelial NO synthase. Hypertension 47, 87-94. Bonaventura, D., Oliveira, F.S., Togniolo, V., Tedesco, A.C., da Silva, R.S. and Bendhack, L.M. (2004). A macrocyclic nitrosyl ruthenium complex is a NO donor that induces rat aorta relaxation. Nitric Oxide 10, 83-91. Bonaventura, D., Oliveira, F.S., da Silva, R.S. and Bendhack, L.M. (2005). Decreased vasodilation induced by a new nitric oxide donor in two kidney one clip hypertensive rats is due to impaired K+ channel activation. Clin. Exp. Pharmacol. Physiol. 32, 478-481.
Bonaventura, D., Lunardi, C.N., Rodrigues, G.J., Neto, M.A. and Bendhack, L.M. (2008). A novel mechanism of vascular relaxation induced by sodium nitroprusside in the isolated rat aorta. Nitric Oxide 18, 287-295.
Bonaventura, D., Lunardi, C.N., Rodrigues, G.J., Neto, M.A., Vercesi, J.A., de Lima, R.G., da Silva, R.S. and Bendhack, L.M. (2009). Endothelium negatively modulates the vascular relaxation induced by nitric oxide donor, due to uncoupling NO synthase. J. Inorg. Biochem. 103, 1366- 1374. Bouloumie, A., Bauersachs, J., Linz, W., Schölkens, B.A., Wiemer, G., Fleming, I. and Busse, R. (1997). Endothelial dysfunction coincides with an enhanced nitric oxide synthase expression and superoxide anion production. Hypertension 30, 934-941.
Cai, H., Li, Z., Davis, M.E., Kanner, W., Harrison, D.G. and Dudley Jr. S.C. (2003). Akt-Dependent Phosphorylation of Serine1179 and Mitogen- Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase 1/2 Cooperatively Mediate Activation of the Endothelial Nitric-Oxide Synthase by Hydrogen Peroxide. Mol. Pharmacol. 63, 325-331.
Callera, G.E., Yogi, A., Tostes, R.C., Rossoni, L.V. and Bendhack, L.M. (2004). Ca2 -activated K channels underlying the impaired acetylcholine-induced vasodilation in 2K-1C hypertensive rats. J. Pharmacol. Exp. Ther. 309, 10361042.
Callera, G.E., Tostes, R.C., Yogi, A., Montezano, A.C.I. and Touyz, R.M. (2006). Endothelin-1-induced oxidative stress in DOCA-salt hypertension involves NADPH-oxidase-independent mechanisms. Clin. Sci. 110, 243-253. Chandra, S., Romero, M.J., Shatanawi, A., Alkilany, A.M., Caldwell, R.B. and Caldwell, R.W. (2012). Oxidative species increase arginase activity in endothelial cells through the RhoA/Rho kinase pathway. Br. J. Pharmacol. 165, 506-519.
Costa, C.A., Amaral, T.A.S., Carvalho, L.C.R.M., Ognibene, D.T., da Silva, A.F.E., Moss, M.B., Valença, S.S., de Moura, R.S. and Resende, A.C. (2GG9). Antioxidant Treatment With Tempol and Apocynin Prevents Endothelial Dysfunction and Development of Renovascular Hypertension. Am.J. Hypertens. 22(12), 1242-1249.
Crimi, E., Ignarro, L.J. and Napoli, C. (2GG7). Microcirculation and oxidative stress. Free Radic. Res. 41, 1364-1375.
Dohi, Y., Hahn, A.W., Boulanger, C.M., Bühler, F R. and Lüscher, T.F. (1992). Endothelin stimulated by angiotensin II augments contractility of spontaneously hypertensive rat resistance arteries. Hypertension 19, 131-137. Ellis, A., Li, C.G. and Rand, M.J. (1998). Effect of xanthine oxidase inhibition on endothelium-dependent and nitrergic relaxations. Eur. J. Pharmacol. 356, 4147.
Endemann, D.H. and Schiffrin, E.L. (2GG4). Endothelial dysfunction. Frontiers in Nephrology. J. Am. Soc. Nephrol. 15, 1983-1992.
Félétou, M., Verbeuren, T.J. and Vanhoutte, P.M. (2GG9). Endothelium-dependent contractions in SHR: a tale of prostanoid TP and IP receptors. Br. J. Pharmacol., 156, 563-574.
Fulton, D., Gratton, J., McCabe, T.J., Fontana, J., Fujio, Y., Walsh, K., Franke, T.F., Papapetropoulos, A. and Sessa, W.C. (1999). Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399, 597-6G1. Gil-Longo, J. and González-Vásquez, C.(2GG5). Characterization of four different effects elicited by H2O2 in rat aorta. Vasc. Pharmacol. 43, 128-138. Gornik, H.L. and Creager, M.A. (2GG4). Arginine and endothelial and vascular healthy. J. Nutr. 134, 288GS-2887S.
Gutterman, D.D., Miura, H. and Liu, Y. (2005). Redox Modulation of Vascular Tone: Focus of Potassium Channel Mechanisms of Dilation. Arterioscler. Thromb. Vasc. Biol. 25, 671-678.
Heitzer, T., Wenzel, U., Hink, U., Krollner, D., Skatchkov, M., Stahl, R.A., MacHarzina, R., Bräsen, J.H., Meinertz, T. and Münzel, T. (1999). Increased NAD(P)H oxidase-mediated superoxide production in Renovascular hypertension: evidence for an involvement of protein kinase C. Kidney Int. 55, 252-260.
Hu, Z., Chen, J., Wei, Q. and Xia, Y. (2008). Bidirectional actions of hydrogen peroxide on endothelial nitric-oxide synthase phosphorylation and function - co-commitment and interplay of Akt and AMPK. J. Biol. Chem. 283, 25256-25263. Laursen, J.B., Rajagopalan, S., Galis, Z., Tarpey, M., Freeman, B.A. and Harrison, D.G. (1997). Role of superoxide in angiotensin II-induced but not catecholamine-induced hypertension. Circulation 95, 588-593. Lin, M.I., Fulton, D., Babbitt, R., Fleming, I., Busse, R., Pritchard, K.A.Jr., Sessa, W.C. (2003). Phosphorylation of threonine497 in endothelial nitric-oxide synthase coordinates the coupling of L-arginine metabolism to efficient nitric oxide production. J. Biol. Chem. 278, 44719-44726.
Lüscher, T.F. and Vanhoutte, P.M. (1986). Endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat. Hypertension 8, 344-348.
Meurer, S., Pioch, S., Gross, S., and Müller-Esterl, W. (2005). Reactive Oxygen Species Induce Tyrosine Phosphorylation of and Src Kinase Recruitment to NO-sensitive Guanylyl Cyclase. J. Biol. Chem. 280 (39), 3314933156.
Mount, P.F., Kemp, B E. and Power, D.A. (2007). Regulation of endothelial and myocardial NO synthesis by multi-site eNOS phosphorylation. J. Mol. Cell Card. 42, 271-279.
Nishi, E.E., Oliveira-Sales, E.B., Bergamashi, C.T., Oliveira, T.G.C., Boim, M.A. and Campos, R.R. (2010). Chronic antioxidant treatment improves arterial renovascular hypertension and oxidative stress markers in the kidney in Wistar rats. Am. J. Hypertens. 23, 473-480.
Pereira, A.C., Ford, P.C., da Silva, R.S. and Bendhack, L.M. (2011). Ruthenium-nitrite complex as pro-drug releases NO in a tissue and enzyme-dependent way. Nitric Oxide 24, 192-198.
Phan, S.H., Gannon, D.E., Varani, J., Ryan, U.S. and Ward, P.A. (1989). Xanthine oxidase activity in rat pulmonary artery endothelial cells and its alteration by activated neutrophils. Am. J. Pathol. 134, 1201-1211. Prysyazhna, O., Rudyk, O. and Eaton, P. (2012). Single atom substitution in mouse protein kinase G eliminates oxidant sensing to cause hypertension. Nature Med. 18 (2), 286-290.
Qu, C., Leung, S.W.S.,Vanhoutte, P.M. and Man, R.Y.K. (2010). Chronic Inhibition of Nitric-Oxide Synthase Potentiates Endothelium-Dependent Contractions in the Rat Aorta by Augmenting the Expression of Cyclooxygenase-2. J. Pharmacol. Exp. Ther 334, 373-380. Rajagopalan, S., Kurz, S., Münzel, T., Tarpey, M., Freeman, B.A., Griendling, K.K. and Harrison, D.G. (1996). Angiotensin II mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone. J. Clin. Invest. 97, 1916 -1923.
Rodrigues, G.J., Lunardi, C.N., Lima, R.G., Santos, C.X., Laurindo, F.R.M., da Silva, R.S. and Bendhack, L.M. (2008). Vitamin C improves the effect of a new nitric oxide donor on the vascular smooth muscle from renal hypertensive rats. Nitric Oxide 18, 176-183.
Romero, M.J., Platt, D.H.,Tawfik, H.E., Labazi, M., El-Remessy, A.B., Bartoli, M., Caldwell, R.B., Caldwell, R.W. (2008). Diabetes-induced coronary vascular dysfunction involves increased arginase activity. Circ. Res. 102, 95-102. Satoh M., Fujimoto,S., Haruna, Y., Arakawa, S., Horike,H., Komai, N., Sasaki, T., Tsujioka, K., Makino, H. and Kashihara, N. (2005). NAD(P)H oxidase and uncoupled nitric oxide synthase are major sources of glomerular superoxide in rats with experimental diabetic nephropathy. Am. J. Physiol. 288, F1144-F1152. Schulz, E., Jansen, T., Wenzel, P., Daiber, A. and Münzel, T. (2008). Nitric oxide, tetrahydrobiopterin, oxidative stress and endothelial dysfunction in hypertension. Ant. Redox Sign. 10, 1115-1126.
Shimokawa, H. (2010). Hydrogen peroxide as an endothelium-derived
hyperpolarizing factor. Pflugers Arch - Eur J Physiol 459, 915-922.
Suzuki, H., Swei, A., Zweifach, B.W. and Schmid-Schönbein, G.W. (1995). In
vivo evidence for microvascular oxidative stress in spontaneously hypertensive
rats. hydroethidine microfluorography. Hypertension 25,1083-1089.
Swei, A., Lacy, F., DeLano, F.A. and Schmid-Schönbein, G.W. (1997).
Oxidative stress in the Dahl hypertensive rat. Hypertension 30, 1628-1633.
Taddei, S., Virdis, A., Ghiadoni, L., Magagna, A. and Salvetti, A. (1997).
Cyclooxygenase inhibition restores nitric oxide activity in essential hypertension.
Hypertension 29, S274-S279.
Taddei, S., Ghiadoni, L., Virdis, A., Versari, D. and Salvetti, A. (2003). Mechanisms of endothelial dysfunction: clinical significance and preventive non-pharmacological therapeutic strategies. Curr. Pharm. Des. 9, 2385-2402. Tang, E.H., Leung, F.P., Huang, Y., Félétou, M., Man, R.Y. and Vanhoutte, P.M. (2007). Calcium and reactive oxygen species increase in endothelial cells in response to releasers of endothelium-derived contracting factor. Br. J Pharmacol. 151, 15-23.
Tang, E.H.C. and Vanhoutte, P.M. (2009). Prostanoid and reactive oxygen species: team players in endothelium-dependent contractions. Pharmacol. Ther. 122, 140-149.
Thomas, D.D., Ridnour, L.A., Isenberg, J.S., Flores-Santana, W., Switzer, C.H., Donzelli, S., Hussain, P., Vecoli, C., Paolocci, N., Ambs, S., Colton, C.A., Harris, C.C., Roberts, D.D. and Wink, D.A. (2008). The chemical biology of nitric oxide: implications in cellular signaling. Free Rad. Biol. Med. 45, 18-31. Tousoulis, D., Antoniades, C., Tentolouris, C., Goumas, G., Stefanadis, C. and Toutouzas, P. (2002). L-arginine in cardiovascular disease: dream or reality? Vasc. Med. 7, 203-211.
Touyz, R.M., Chen, X., Tabet. F., Yao, G., He, G., Quinn, M.T., Pagano, P.J. and Schiffrin, E.L. (2002). Expression of a functionally active gp91phox-containing neutrophil-type NAD(P)H oxidase in smooth muscle cells from human resistance arteries: regulation by angiotensin II. Circ. Res. 90, 1205-1213. Vanhoutte, P.M. (2011). Endothelium-dependent contractions in hypertension: when prostacyclin becomes ugly. Hypertension 57, 526-531. Vaziri, N.D. (2004). Roles of oxidative stress and antioxidant therapy in chronic kidney disease and hypertension. Curr. Opin. Nephrol. Hypertens. 13, 93-99.
Wu, K.K. and Liou, J. (2005). Cellular and molecular biology of prostacyclin synthase. Biochemical and Biophysical Research Communications 338, 45-52. Zhang, C., Hein, T.W., Wang, W., Miller, M.W., Fossum, T.W., McDonald, M.M., Humphrey, J.D. and Kuo, L. (2004). Upregulation of vascular arginase in hypertension decreases nitric oxide-mediated dilation of coronary arterioles. Hypertension 44, 935-943.
Zhou, X., Bohlen, H.G., Miller, S.J. and Unthank, J.L. (2008). NAD(P)H oxidase-derived peroxide mediates elevated basal and impaired flow-induced NO production in SHR mesenteric arteries in vivo. Am. J. Physiol. 295, H1008-H1016.
Zou, M.H., Hou, X.Y., Shi, C.M., Nagata, D., Walsh, K. and Cohen, R.A. (2002a). Modulation by peroxynitrite of Akt- and AMP-activated kinase-
A A -7Q
dependent Ser11'9 phosphorylation of endothelial nitric oxide synthase. J. Biol. Chem. 36, 32552-32557.
Zou, M.H., Shi, C. and Cohen, R.A. (2002b). Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J. Clin. Invest. 109, 817-826.
Figure 1. Sources of reactive oxygen species (ROS) and proposed mechanisms for their contribution to EDRFs and EDCFs releasing involved in the control of vascular tone in isolated vessels from normotensive (A) and hypertensive (B) animals.
Copyright of Frontiers in Physiology is the property of Frontiers Media S.A. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
