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Symposium Report |
1 Canadian Institutes for Health Research Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Quebec, Canada
Abstract
Resistance arteries undergo structural changes (vascular remodelling) in hypertension. These changes involve media thickening, reduced lumen diameter and consequent increased media:lumen ratio. Cellular processes underlying these events include altered vascular smooth muscle cell (VSMC) growth, migration, differentiation and increased extracellular matrix abundance. Another factor contributing to remodelling is inflammation, associated with macrophage infiltration, fibrosis and increased expression of redox-sensitive pro-inflammatory genes. Among the factors involved in arterial remodelling, angiotensin (Ang) II appears to be one of the most important. Ang II, a multifunctional peptide with pleiotropic actions, modulates vasomotor tone, cell growth, apoptosis/anoikis, cell migration and extracellular matrix deposition. It is pro-inflammatory and it stimulates production of growth factors and vasoactive agents. The multiple actions of Ang II are mediated via complex intracellular signalling pathways including stimulation of the phosholipase C (PLC)–inositol 1,4,5-trisphosphate (IP3)–1,2-diacylglycerol (DAG) cascade, mitogen-activated protein (MAP) kinases, tyrosine kinases and RhoA/Rho kinase. Furthermore, Ang II elicits many of its (patho)physiological effects by stimulating reactive oxygen species (•O2– and H2O2) generation through activation of vascular NAD(P)H oxidase. •O2– and H2O2 in turn influence downstream signalling molecules including transcription factors, tyrosine kinases/phosphatases, Ca2+ channels and MAP kinases. Interaction between these systems is complex and dysregulation at any level may contribute to vascular remodelling. Targeting such molecules/pathways could prevent or induce regression of hypertensive vascular damage thereby ameliorating development of hypertension and preventing target organ damage. The present review discusses the role of Ang II in remodelling of resistance arteries, focusing on some signalling pathways involved in vascular growth and inflammation in hypertension.
(Received 1 April 2005;
accepted after revision 10 May 2005; first published online 12 May 2005)
Corresponding author R. Touyz: Canada Research Chair in Hypertension, Kidney Research Centre, Ottawa Health Research Institute/University of Ottawa, Room 1333A, 451 Smyth Road, Ottawa, K1H 8M5, Ontario, Canada. Email: rtouyz{at}uottawa.ca
Resistance arteries (100–300 µm in diameter) respond to physiological and pathophysiological stimuli to maintain perfusion according to the metabolic needs of tissues. Vasomotor control (contraction/relaxation) is responsible for rapid adaptation of lumen diameter, whereas alterations in structural properties of the vascular wall constitute a dynamic process occurring in response to long-term haemodynamic modifications. Initially structural changes are adaptive, but subsequently become maladaptive resulting in changes in media thickness and lumen diameter. This process, called vascular remodelling, contributes to the pathophysiology of vascular diseases, including hypertension (Mulvany et al. 1996).
Vascular remodelling is associated with alterations of the luminal diameter (outward or inward) and changes in tunica media mass (hypertrophic, eutrophic or hypotrophic), due to increased transmural pressure and blood flow (Mulvany et al. 1996). Increased arterial pressure induces eutrophic inward remodelling, corresponding to re-organization of cellular and non-cellular material of existing vascular wall around a smaller radius, or hypertrophic inward remodelling due to an increase in wall cross-sectional area. In essential hypertension and in the spontaneously hypertensive rat (SHR), resistance arteries exhibit mainly inward eutrophic remodelling, whereas in secondary hypertension hypertrophic remodelling predominates (Intengan & Schiffrin, 2001). In angiotensin (Ang) II-induced hypertension, both eutrophic and hypertrophic remodelling have been described (Virdis et al. 2004). Probably combined forms of remodelling co-exist in different vascular beds and at different time points in the development of hypertension.
Changes in blood flow mainly affect lumen dimensions. Chronic high blood flow or increased wall stress results in outward hypertrophic remodelling with increased lumen diameter and media mass (De Mey et al. 2005). On the other hand, long-term decrease in blood flow leads to reduced media mass with consequent hypotrophic remodelling. Vascular remodelling in response to changes in blood flow occurs in physiological conditions such as development, exercise and pregnancy and in pathological conditions, such as arterial occlusive disease and arteriovenous fistula.
Whether increased pressure itself or other factors initiate the process of vascular remodelling is unclear. However, the endothelium is probably important as it serves as a sensor of haemodynamic and humoral factors and is a moderator of signals to underlying vascular smooth muscle cells (VSMCs), which are key players in the remodelling process. Altered VSMC growth/apoptosis, contraction/relaxation, migration and differentiation, impaired production and degradation of extracellular matrix and stimulation of inflammatory responses result in structural remodelling. Cellular mechanisms and intracellular signalling events implicated in arterial remodelling in hypertension are complex, but Ang II is among the many systems shown to be important (Schiffrin & Touyz, 2004) (Fig. 1).
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B (NF-B), AP-1 and Ref-1 (Touyz, 2000; Sanz-Rosa et al. 2005). Through these actions Ang II augments vascular inflammation and promotes endothelial dysfunction and structural remodelling. The present review discusses the importance of Ang II in arterial remodelling in hypertension focusing specifically on signalling events contributing to VSMC growth and vascular inflammation. Ang II, arterial remodelling and inflammation
VSMCs, critically involved in maintaining vascular integrity, are dynamic, multifunctional cells, contributing to arterial remodelling through numerous processes, including hyperplasia (increased VSMC number, associated with DNA synthesis), hypertrophy (enlargered cell size, associated with increased protein synthesis and intracellular volume), apoptosis, cell elongation, re-organization, altered production of extracellular matrix proteins and inflammation (Berk, 2001).
Increasingly it has been recognized that inflammation participates in vascular remodelling (Virdis & Schiffrin, 2003) and that it may contribute to accelerate vascular damage in cardiovascular diseases. Whether Ang II or blood pressure elevation by itself, through effects on adhesion molecules, chemokines and cytokines induced by cyclic mechanical strain, are associated with the inflammatory response, still remains unclear. Inflammation may activate the renin–angiotensin system (RAS) and thereby further contribute to remodelling and hypertension (Virdis & Schiffrin, 2003). Activators of nuclear receptors, such as the peroxisome proliferator activated receptors (PPARs), which are hypolipidaemic agents (the fibrates, PPAR
agonists) or insulin sensitizers (glitazones, PPAR
agonists), down-regulate the vascular inflammatory response in experimental animals and decrease serum markers of inflammation in humans (Diep et al. 2002). Thus, PPARs and vasoactive substances may be endogenous inflammatory modulators in hypertension.
Vascular inflammation is characterized by recruitment of monocytes and lymphocytes into the subendothelial space, production of chemotactic cytokines, increased expression of adhesion molecules, VSMC proliferation and altered extracellular matrix production and degradation. These processes, together with lipid oxidation, are pro-atherogenic, particularly in injured arteries in hypertension. Ang II has significant pro-inflammatory actions in the vascular wall, inducing the production of ROS, cytokines, adhesion molecules and activation of redox-sensitive inflammatory genes (Suematsu et al. 2002). Ang II also modulates expression of pro-inflammatory molecules in the vessel wall, such as vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM) and E-selectin through redox-dependent pathways (Pueyo et al. 2000). In VSMCs, Ang II stimulates VCAM-1 production, chemokine monocyte chemotactic protein (MCP)-1 and the cytokine interleukin (IL)-6, which stimulates recruitment of mononuclear leucocytes into the vessel media. Many of these factors are increased in plasma from hypertensive patients and may reflect vascular inflammation and target organ damage (Hlubocka et al. 2002).
Ang II signalling inVSMCs
Ang II mediates effects via complex intracellular signalling pathways that are stimulated following binding of the peptide to its cell-surface receptors, of which two major subtypes have been cloned and characterized, AT1R and AT2R (Touyz & Schiffrin, 2000; Murphy et al. 1991). In humans, AT1R is widely expressed in blood vessels, heart, kidney, adrenal glands and liver, whereas AT2R is present mainly in fetal tissue, decreasing rapidly after birth, with relatively low amounts normally expressed in adult tissue. In pathological conditions associated with cardiac and vascular remodelling or inflammation, AT2R expression is up-regulated. Both receptors play a role in regulating VSMC function, although they differ in their actions. While the AT1R is associated with growth, inflammation and vasoconstriction, the AT2R is generally associated with opposite actions stimulating apoptosis and vasodilatation (Touyz & Schiffrin, 2000).
Growth signalling by Ang II.
Ang II stimulates cell growth through phosphorylation of tyrosine kinases, activation of mitogen-activated protein (MAP) kinases, mobilization of intracellular Ca2+ and production of ROS (Touyz & Schiffrin, 2000) (Fig. 2). Ang II, via AT1Rs, induces phosphorylation of multiple tyrosine kinases, including c-Src, janus family kinases (JAK), focal adhesion kinase (FAK), Pyk2, p130Cas and phosphatidylinositol 3-kinase (PI3K) (Touyz et al. 1999; Eguchi & Inagami, 2000). Findings from our laboratory in human and rat VSMC identified c-Src as a critically important kinase involved in trophic and contractile actions of Ang II (Touyz et al. 2001b; Touyz et al. 2003). We also showed that Ang II-induced activation of c-Src is augmented and that this is associated with increased cell growth in human and experimental hypertension (Touyz et al. 2001a; Touyz et al. 2002b). c-Src is a major regulator of numerous downstream targets, including MAP kinases, PLC-, Pyk2, FAK, JAK, the protein Shc, PI3K and NAD(P)H oxidase. These proteins influence cell survival, metabolism, cytoskeletal re-organization and membrane trafficking and have been identified as having important growth promoting and anti-apoptotic actions.
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Ang II also activates receptor tyrosine kinases, even though it may not bind directly to these receptors. This process of transactivation has been demonstrated for the epidermal growth factor (EGF) receptor, platelet-derived growth factor (PDGF) receptor and insulin-like growth factor (IGF)-1 receptor (Saito & Berk, 2001). Mechanisms whereby Ang II induces transactivation include activation of tyrosine kinases (Pyk2 and Src), redox-sensitive processes and possibly through matrix metalloproteinases (MMPs) that release heparin-binding EGF (Saito & Berk, 2001). Ang II also increases production of vasoactive hormones and growth factors in hypertension, such as endothelin (ET)-1, PDGF, transforming growth factor (TGF)ß, basic fibroplast growth factor (bFGF) and IGF-1, which could promote cell proliferation, protein synthesis and fibrosis, further contributing to growth processes in remodelling.
Ang II signalling through reactive oxygen species. Ang II mediates many of its cellular actions by stimulating formation of intracellular ROS, which are highly reactive, bioactive, short-lived molecules derived from the reduction of molecular oxygen (Taniyama & Griendling, 2003) (Fig. 3). ROS play an important role in modulating inflammatory reactions. Major ROS produced within vascular cells include superoxide anion (•O2–), hydrogen peroxide (H2O2), hydroxyl radical (•OH), nitric oxide (NO) and peroxynitrite (ONOO–) (Taniyama & Griendling, 2003). ROS are implicated at virtually every stage in the inflammatory response, including vascular permeability, leucocyte adhesion and transmigration, chemotaxis, cell growth and fibrosis (Harrison et al. 2003; Touyz, 2000). These processes are mediated via multiple redox-sensitive signalling pathways.
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2O2
+ NAD(P)H + H+. The prototypical NAD(P)H oxidase is that found in phagocytes, which comprises five components: (phox for PHagocyte OXidase) p47phox, p67phox, p40phox, p22phox and gp91phox and the small G-proteins Rac 1/2. Unlike phagocytic NAD(P)H oxidase, which is activated only upon stimulation and which generates •O2– in a burst-like manner extracellulary, vascular oxidases are constitutively active, produce •O2– intracellulary in a slow and sustained fashion and act as intracellular signalling molecules, influencing not only transcription factors, but other molecules involved in inflammation, such as MAP kinases, tyrosine kinases and protein phosphatases (Lassegue & Clempus, 2003; Touyz et al. 2002a). All of the phagocytic NAD(P)H oxidase subunits are expressed, to varying degrees, in vascular cells. The newly discovered gp91phox (nox2) homologues, nox1 and nox4 (Nox for NAD(P)H oxidase) have also been detected in the vasculature (Lassegue & Clempus, 2003; Griendling, 2004). Nox1 has been implicated in cell growth, Nox4 in delayed cell growth and gp91phox may act as a proton pump in addition to being part of the NAD(P)H oxidase complex (Griendling, 2004). Whereas Ang II up-regulates Nox1 and gp91phox, it seems to down-regulate Nox4. Moreover whereas gp91phox is primarily cell membrane-associated, Nox1 localizes in caveolae and Nox4 in focal adhesion (Hilenski et al. 2004). Ang II is a potent stimulator of vascular NAD(P)H oxidase (Griendling et al. 1994). It induces activation of the enzyme, it increases expression of NAD(P)H oxidase subunits and it stimulates ROS production in cultured VSMCs and intact arteries. Mechanisms linking Ang II to the enzyme and upstream signalling molecules modulating vascular NAD(P)H oxidase include phospholipase D (PLD), phospholipase A2 (PLA2), protein kinase C (PKC), c-Src, PI3K and Rac (Lassegue & Clempus, 2003). In hypertension, these processes are augmented contributing to increased activation of the oxidase and consequent oxidative stress. Furthermore, various polymorphisms in the promoter of the p22(phox) gene have been identified in hypertensive patients, which may also play a role in increased NAD(P)H-driven generation of •O2– in hypertension (San Jose et al. 2004).
Superoxide and H2O2 activate multiple signalling molecules, including MAP kinases (p38MAP kinase, JNK, ERK-5 and ERK1/2), non-receptor tyrosine kinases (Src, JAK2, STAT, p21Ras, Pyk2 and Akt), receptor tyrosine kinases (EGFR, IGFR and PDGFR), protein tyrosine phosphatases and redox-sensitive transcription factors (NF-B, AP-1 and hypoxia-inducible factor (HIF)-1) (Nathan, 2003). Activation of these molecules participates in cell growth, migration, expression of pro-inflammatory genes, production of extracellular matrix proteins and contraction, which contribute to arterial remodelling in hypertension. Exact mechanisms whereby ROS modify signalling molecules remain unclear, but oxidative modification of proteins is important (Nathan, 2003).
Inhibition of NAD(P)H oxidase activity is now being considered, at least experimentally, as a possible therapeutic target in the treatment of hypertension (Hamilton et al. 2004). In fact it has been suggested that some of the beneficial actions of classical antihypertensive drugs may be mediated, in part, by decreasing vascular oxidative stress. These effects have been attributed to direct inhibition of NAD(P)H oxidase activity and to intrinsic antioxidant properties of the agents.
Conclusions
Structural alteration or remodelling of resistance arteries is a hallmark of hypertension. Initial factors contributing to this process involve increased transmural pressure, changes in blood flow and endothelial dysfunction. Subsequent alterations of VSMC growth, migration, differentiation, production of extracellular matrix proteins and inflammation are then responsible for the resulting vascular remodelling. Of the numerous factors influencing remodelling in hypertension, Ang II appears to be one of the most important. Over the recent past our views of Ang II have changed from being a simple vasoconstrictor to that of a complex growth factor mediating effects through diverse signalling pathways. It has also become clear that Ang II is a key player in vascular inflammation. Through increased generation of ROS and activation of redox-sensitive transcription factors, Ang II promotes expression of cell adhesion molecules and induces synthesis of pro-inflammatory mediators and growth factors. These processes facilitate increased vascular permeability, leucocyte recruitment and vascular fibrosis leading to vascular injury and structural remodelling. Targeting some of these signalling events with novel therapeutic strategies that would lead to the regression or prevention of arterial remodelling may provide important vascular protection in hypertension and other forms of cardiovascular disease.
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Acknowledgements
Studies performed by the author were supported by grants 57786 and 44018 and a grant to the Multidisciplinary Research Group on Hypertension, all from the Canadian Institutes of Health Research.
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