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Cardiovascular Research 2002 55(1):16-24; doi:10.1016/S0008-6363(02)00221-3
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Copyright © 2002, European Society of Cardiology

The wnt-frizzled cascade in cardiovascular disease

Marielle E. van Gijna, Mat J.A.P. Daemenb, Jos F.M. Smitsa and W.Matthijs Blankesteijna,*

aDepartment of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
bDepartment of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands

* Corresponding author. Tel.: +31-43-388-1417; fax: +31-43-388-4149 wm.blankesteijn{at}farmaco.unimaas.nl

Received 22 June 2001; accepted 17 December 2001

KEYWORDS Angiogenesis; Developmental biology; Infarction; Signal transduction


   1. Introduction
Top
 1. Introduction
2. Brief outline of...
 3. The wnt-frizzled pathway...
 4. The wnt-frizzled cascade...
 5. The wnt-frizzled cascade,...
 6. The wnt-frizzled cascade...
 7. Conclusions
 References
 
Wnt-proteins constitute a family of secreted cystein-rich glycosylated proteins, involved in a variety of modeling and remodeling processes including cell proliferation, differentiation, apoptosis and the control of cell orientation [1–3]. Malfunctioning of the wnt-frizzled pathway has been implied in diseases as divergent as cancer and Alzheimer's disease [1,4]. The wnt-frizzled signal transduction pathway plays an important role during non-vertebrate and vertebrate development [5]. Several studies have shown the importance of wnts in the control of processes such as patterning of the body axis and development of the central nervous system and the limbs [6,7]. Moreover, interventions in wnt signaling have been described to affect cardiac morphogenesis [8,9] and several members of the wnt-frizzled signal transduction pathway were found to be expressed during cardiac development in vertebrates [10–14].

In cardiovascular pathology, re-expression of a fetal gene expression pattern is a generally observed phenomenon [15]. The study of gene expression during development may therefore provide clues about the expression profile during cardiovascular pathology. Recently, considerable progress has been made concerning the role of the wnt-frizzled signal transduction pathway in the development and progression of cardiovascular pathology. This review will focus on the possible role of the wnt-frizzled signal transduction pathway in cardiovascular diseases.


   2. Brief outline of the wnt-frizzled cascade
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 1. Introduction
 2. Brief outline of...
3. The wnt-frizzled pathway...
 4. The wnt-frizzled cascade...
 5. The wnt-frizzled cascade,...
 6. The wnt-frizzled cascade...
 7. Conclusions
 References
 
The family of wnt proteins consists of 16 members [5]. These proteins are extremely difficult to purify because they tend to bind to the extracellular matrix [16], which hampers the study of their characteristics. An overview of the wnt proteins and their proposed function during development, derived from the study of null mutants, is provided in Table 1. Based on functional differences, wnt proteins can be divided into two classes, the wnt1 class and the wnt5a class. Members of the wnt1 class are able to induce duplication of the body axis early during the embryogenesis of Xenopus, whereas members of the wnt5a class can affect morphogenetic movements and can be considered to antagonize the members of the wnt1 class [17–19]. These different effects of the two classes of wnt proteins are probably reflected by their proposed signal transduction mechanisms: Wnt proteins from the wnt1 class preferentially signal through β-catenin, generally referred to as the canonical pathway, whereas wnt proteins from the wnt5a class can stimulate intracellular Ca2+ release, the so-called non-canonical or wnt/Ca2+ pathway [20].


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  		Table 1 Wnt homologues and their functional differences

 
Wnt proteins can act as ligands for frizzled proteins, a family of 7-transmembrane (7-TM) receptors [21] consisting of at least ten members. As shown in Table 2, frizzled receptors are widely expressed in the cardiovascular system as well as in other organs. Little is known about the functional role of frizzled receptors in normal development, because only null mutants for frizzled-4 and frizzled-5 have been described so far [22,23]. Mice lacking the frizzled-4 gene suffer from progressive cerebellar degeneration together with auditory and esophageal dysfunction, whereas targeted disruption of the frizzled-5 gene is lethal early during embryogenesis.


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  		Table 2 Mammalian frizzled homologues and their expression pattern

 
Although frizzled receptors share their topology with the well-known 7-TM receptors, a remarkable difference between frizzled receptors and classical 7-TM receptors is that a well-conserved extracellular cystein-rich domain (CRD) is implicated in ligand binding of the frizzled receptors, and that frizzled receptors use proteins homologous to the Low Density Lipoprotein (LDL) receptor as co-receptors in wnt binding [24–26]. In Drosophila, frizzled receptors have been shown to be able to receive signals that determine the orientation of the cell in relation to its neighbors, signals that are referred to as polarity signals, and to be capable of relaying these signals to neighboring cells [27]. In the meantime, other functions have been described for frizzled receptors, including modulation of cell proliferation through β-catenin [5] and induction of apoptosis [28].

More and more information is becoming available about the signal transduction pathways of frizzled receptors (Fig. 1). A central molecule in these pathways is dishevelled (dvl) [29], for which three mammalian homologues have been described. The biochemical mechanism through which dishevelled can transduce the signal still remains to be resolved, although there is evidence for hyperphosphorylation and translocation of the dvl protein from the cytoplasm to the cell membrane in response to wnt [30,31]. Activation of dvl proteins can stimulate several signal transduction pathways [32], including the canonical pathway which leads to degradation of Armadillo/β-catenin (Armadillo is the Drosophila homologue of β-catenin), and activation of c-Jun N-terminal kinase [33]. Non-canonical signaling of frizzled receptors through intracellular Ca2+ release, leads to activation of two kinases, Ca2+-calmodulin-dependent protein kinase II and protein kinase C, and is probably G-protein dependent [20]. The different frizzled receptors have been shown to preferentially activate either the canonical or non-canonical pathway, as shown in Table 2, although there are reports that a single frizzled subtype can activate different pathways [20].


Figure 1
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  		Fig. 1 The canonical signal transduction pathway of frizzled receptors. Proteins form the wnt family can bind to frizzled receptors This causes an activation of the signal transduction molecule dishevelled (dvl) which in turn inhibits the enzyme glycogen synthase kinase 3-β (GSK3-β). This enzyme is responsible for the phosphorylation of β-catenin, a protein that can act as a second messenger in this cascade. β-Catenin is phosphorylated in a complex with, among other components, Axin and adenomatous polyposis coli (APC) protein, which is a first step in its degradation by the ubiquitin proteasome pathway. β-Catenin can activate transcription factors from the T-cell factor/lymphocyte enhancer factor (TCF/LEF) family, and can form a complex with {alpha}-catenin and members cadherin family at the plasma membrane. sFRPs (soluble frizzled-related proteins) share the wnt binding domain with frizzled receptors but lack the transmembrane domain. sFRPs can bind wnt proteins, thereby preventing the interaction with frizzled receptors.

 

   3. The wnt-frizzled pathway and cardiac wound healing after myocardial infarction
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 1. Introduction
 2. Brief outline of...
 3. The wnt-frizzled pathway...
4. The wnt-frizzled cascade...
 5. The wnt-frizzled cascade,...
 6. The wnt-frizzled cascade...
 7. Conclusions
 References
 
An example of a cardiovascular disease in which cell proliferation and migration play an important role is wound healing after myocardial infarction (MI). This wound healing process is a complex cascade of events [34], which includes the migration and proliferation of fibroblast-like cells into the infarct area [35,36]. The fibroblast-like cells are responsible for the deposition of the extracellular matrix in the granulation tissue that is formed in the infarct area, but in contrast to normal fibroblasts these cells also possess contractile properties and are therefore referred to as myofibroblasts [37]. When the granulation tissue matures into a scar, the myofibroblasts can be found in organized arrays, aligned with the epi- and endocardium. It has been suggested that the contractile properties and the striking degree of organization of (myo)fibroblasts contribute to the preservation of cardiac function by preventing the dilatation of the infarct area [37,38], although the mechanism(s) that govern the architectural control of the many processes involved in infarct healing are poorly understood.

In a study from our group, myofibroblasts have been shown to express frizzled 2 during their migration and proliferation after MI in rats [39], and we have observed the expression of dvl1 in the myofibroblasts in the infarct area [40]. The expression of frizzled 2 was restricted to the migratory phase of the myofibroblasts, which has led us to the hypothesize that frizzled is involved in the alignment process of (myo)fibroblasts [39] during the process of infarct healing after MI, which is depicted in Fig. 2. We have tested this hypothesis by inducing MI in mice lacking the dvl1 gene (dvl1–mice), and observed infarct rupture in 75% of the dvl1–mice in the first week after MI, whereas in wildtype mice this percentage was below 10%. Infarct rupture was associated with undetectable levels of β-catenin in the intercalated discs of the viable cardiomyocytes, determined by immunohistochemistry, whereas β-catenin was readily detectable in the hearts from the wildtype mice that did not die from infarct rupture [41]. This suggests that a lack of β-catenin in the adherens junctions of cardiomyocytes results in an impaired structural integrity of the heart, which apparently does not cause complications under normal physiological conditions. However, when the heart is severely challenged through the induction of MI, the myocyte–myocyte interactions appear to be insufficiently strong to maintain the integrity of the ventricular wall. In general, from these combined studies it can be concluded that a functional wnt-frizzled cascade is a prerequisite for an adequate infarct healing.


Figure 2
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  		Fig. 2 Time course of the wound healing response after myocardial infarction in rats and mice. (A) After 12–18 h cardiomyocytes die due to necrosis or apoptosis. (B) About 24 h after the onset of the infarct, polymorphonuclear neutrophils infiltrate the necrotic area. (C) After 1–2 weeks the infarct contains granulation tissue with prominent capillaries, myofibroblasts and macrophages. The necrotic debris has been largely removed and a small amount of collagen has been deposited. (D) Starting at about 3 weeks after MI, the granulation tissue begins to mature into a scar, characterized by the deposition of large amounts of collagen fibers. In the right column, the components of the wnt-frizzled cascade are indicated that are expressed during the phase of granulation tissue formation.

 

   4. The wnt-frizzled cascade and angiogenesis/neovascularization
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 References
 
Angiogenesis is an important process in ischemic heart disease; it is essential for the restoration of the blood supply to the infarct area after myocardial infarction. In vitro experiments suggested that the wnt-frizzled pathway is involved in the proliferation of endothelial cells. Over-expression of wnt1 in a primary endothelial cell culture resulted in the proliferation of these cells, induced an increase in the pool of free β-catenin and increased LEF/TCF mediated gene transcription [42]. These data suggest a role for the wnt-frizzled cascade in the formation and differentiation of the vasculature. This conclusion is supported by the observation that in mice that lack the fzd5 gene, defects in yolk sac angiogenesis are present which result in embryonic death around 10.75 days post coitum [23].

The regulation of the cellular β-catenin content by the wnt-frizzled cascade involves the enzyme GSK-3β (Fig. 1). When the wnt-frizzled cascade is inactive, GSK-3β phosphorylates serine and threonine residues of β-catenin, in a complex with many other proteins including the scaffold protein axin and adenomatous polyposis coli (APC) protein. Phosphorylation is the first step in the degradation of β-catenin by the ubiquitin proteasome pathway. When the wnt-frizzled cascade becomes activated, the activity of GSK-3β is inhibited, resulting in increased levels of intracellular β-catenin [5]. Moreover, recent data suggest that the a modulation of the cytoplasmic β-catenin content can affect the β-catenin bound to the plasma membrane in adherens junctions [12,43]. This anticipates a dual role for the wnt-frizzled pathway: on the one hand, the nuclear β-catenin regulates the cell proliferation by turning on cell cycle regulators, whereas on the other hand β-catenin at the plasma membrane regulates cell adhesion.

Vascular endothelial growth factor (VEGF) is a major modulator of angiogenesis and is known to play a key role during the development of new blood vessels after MI [44,45]. In vitro, VEGF can stimulate tyrosine phosphorylation of β-catenin in endothelial cells [46], which is associated with disruption of the β-catenin/cadherin complex in the adherens junctions [47]. Disruptions of cell adhesion complexes are essential for the migration of endothelial cells into the newly formed vessel, so the stimulation of blood vessel formation after MI by VEGF may, at least in part, be β-catenin-dependent.

In a recent in vivo study, we have observed that during the neovascularization after MI, β-catenin is translocated from the plasma membrane to the cytoplasm of endothelial cells during the phase of neovascularization of the infarct area [48]. The expression of dvl1 in these cells, simultaneous with the appearance of cytoplasmic β-catenin, provides further evidence that the wnt-frizzled cascade plays a role in the neovascularization process after MI.

When all the data are taken together, there is increasing evidence from both in vivo and in vitro studies that the wnt-frizzled cascade is involved in the formation of new blood vessels. The putative link between VEGF and β-catenin opens opportunities for new lines of research, which will lead to a better understanding of the process of angiogenesis. Moreover, these results suggest that frizzled receptors can be considered as therapeutic targets to modulate blood vessel formation.


   5. The wnt-frizzled cascade, cardiac hypertrophy and heart failure
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 1. Introduction
 2. Brief outline of...
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 4. The wnt-frizzled cascade...
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6. The wnt-frizzled cascade...
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When faced with an increased work load, cardiomyocytes exert a hypertrophic response, which can be mimicked in rats by a partial occlusion of the aorta. It is well established that hypertrophy development coincides with the expression of the proto-oncogenes c-fos, c-myc and c-jun, which are thought to regulate this process [15]. During the development of hypertrophy in the rat heart, frizzled-2 expression was found to be upregulated [49]. Interestingly, the regulation of c-jun expression by β-catenin has been observed in colorectal carcinomas [50]. Although this is suggestive for a link between the wnt-frizzled pathway and the regulation of the development of cardiac hypertrophy it is not clear yet how frizzled-2, reported to couple preferentially to the non-canonical pathway, can regulate the cellular β-catenin content in this setting.

Re-expression of a fetal gene expression pattern is well documented during the development of cardiac hypertrophy [15]. Therefore, the study of gene expression during cardiac development can help to better understand the mechanisms underlying the hypertrophic response. Recent studies in Xenopus and chick have shown that cardiogenesis in the anterior lateral mesoderm is inhibited by signals from the neural tube, and that this blockade can be mimicked by expression of wnt-1 or wnt-3a [51]. Antagonists of the wnt pathway, like dickkopf-1 and crescent, are necessary for the normal induction of heart formation in this area. Normal heart induction could also be induced by ectopic expression of GSK-3β, confirming the involvement of the canonical wnt pathway in this process [52]. From additional experiments in chickens it was concluded that inhibition of wnt signaling promotes heart formation in the anterior lateral mesoderm, whereas active wnt signaling in the posterior lateral mesoderm promotes blood development [53].

Using cultured cardiomyocytes, Haq et al. have recently shown that inactivation of GSK-3β by phosphorylation of a serine residue at position 9, plays a crucial role in the development of hypertrophy [54]. Over-expression of a constitutively active GSK-3β mutant, lacking the serine at position 9, prevented the hypertrophic response to endothelin-1 and phenylephrine. Interestingly, the hypertrophic response to these compounds could be restored by inhibiting the GSK-3β mutant with LiCl. Moreover, inhibition of GSK-3β was also observed in failing human hearts, but not in compensated cardiac hypertrophy [55]. Collectively, the data suggest a role for GSK-3β in hypertrophic response observed in the heart, probably through the activation of proto-ongogenes.

Schumann et al. have studied the expression of soluble Frizzled-Related Proteins (sFRPs) in the failing human heart. sFRPs represent a family of secreted proteins containing a CRD similar to that of frizzleds [56], but lack a transmembrane domain and therefore are not bound to the plasma membrane. sFRPs are proposed to bind wnts which circulate in the interstitium, thereby preventing interaction between wnts and frizzled receptors [56–58]. The family consists of at least 5 members, and is referred to with many names in the literature: Frizbee, Fritz, Soluble Apoptosis-Related Protein (SARP) and Sizzled. In their study, Schumann et al. found the levels of sFRP-3 and -4 to be elevated in hearts of patients with dilated cardiomyopathy and coronary heart disease compared to non-failing donor hearts, suggesting an inhibition of the wnt-frizzled cascade in failing myocardium [59]. This observation seems to be in contrast with the results of Haq et al. [55], who showed inhibition of GSK-3β in failing human hearts, which could be indicative for an activation of the wnt-frizzled cascade, leaving the question of an activated or inhibited cascade open for further study.


   6. The wnt-frizzled cascade and arterial injury
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 1. Introduction
 2. Brief outline of...
 3. The wnt-frizzled pathway...
 4. The wnt-frizzled cascade...
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 6. The wnt-frizzled cascade...
7. Conclusions
 References
 
Endothelial cells play a major role in the development of atherosclerosis, a vascular disease that involves endothelial dysfunction, neutrophil and macrophage migration and differentiation into foam cells, and smooth muscle cell migration and proliferation. Damaged endothelium has been proposed to be an important mediator in the onset of the disease, and atherosclerotic plaques are most frequently found in specific parts of the arterial tree where asymmetries in the velocity profiles occur. The adherens junctions between the endothelial cells play an important role in maintaining the endothelial barrier function.

Endothelial cells exhibit profound changes in cell shape in response to shear stress, which requires disassembly and reassembly of adherens junction proteins. It has been shown that within hours after application of shear stress the junctional localization of {alpha}-catenin and β-catenin becomes punctuated and less intense, suggesting that the shear stress-induced changes in endothelial cells could have important implications for the control of the permeability of the endothelial barrier [60]. In another study it was shown that activated neutrophils increase the permeability of cultured bovine coronary endothelial cells. Remodeling of adherens junctions was involved in this increased permeability since the β-catenin and VE-cadherin staining changed from a uniform distribution to a diffuse pattern along the membrane. Furthermore, it was shown that the tyrosine phosphorylation of the adherens junction proteins was significantly increased in the endothelial cells that were exposed to neutrophils [61]. These data point to a role of the wnt-frizzled cascade in adherens junction remodeling.

In an experimental model of arterial injury, the rat aorta balloon injury model, the expression of two frizzled receptors and the sFRP Rfzb-1 was altered. Rfzb-1 expression was significantly upregulated from 2 to 7 days after balloon injury. The frizzled-1 and -2 expression was downregulated 1 h after balloon injury, but 2 days after balloon injury the expression had returned to the level observed in the de-endothelialized aorta which served as a control in this study [62]. Using bovine endothelial cells, Duplaa et al. observed high expression levels of the sFRP-1 orthologue FrzA in non-proliferating, polarized vascular endothelial cells, but low expression of FrzA in proliferating cultured vascular endothelial cells. When the cells became confluent, FrzA expression increased again [63]. The changes in expression profile of the sFRPs during arterial injury are highly suggestive for a role of wnt proteins in this process. sFRPs can bind wnt proteins and prevent interaction with frizzled receptors, allowing the local fine-tuning of wnt signaling in the different parts of the remodeling artery. However, additional experiments will be needed to further identify the subtypes of wnt and frizzled proteins involved in arterial response to injury.


   7. Conclusions
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 1. Introduction
 2. Brief outline of...
 3. The wnt-frizzled pathway...
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 5. The wnt-frizzled cascade,...
 6. The wnt-frizzled cascade...
 7. Conclusions
References
 
While much work has been done in neoplastic diseases and embryology, the role of the wnt-frizzled signal transduction pathway in cardiovascular disease has only recently begun to be explored. Originally, most reports focussed on the role of β-catenin in the regulation of gene transcription and cell proliferation, but the attention for its role in the regulation of cell adhesion is increasing. The studies in cardiovascular diseases suggest that this is an important function for β-catenin in endothelial cells as well as cardiomyocytes. The experimental data suggest that stimulation of the wnt-frizzled cascade in endothelial cells would be beneficial for neovascularization. Furthermore, expression of components of the wnt-frizzled cascade in myofibroblasts during infarct healing suggests a role in the architectural control of this process, and the infarct rupture observed in the dvl1 knockout mice underscores the importance of a functional wnt-frizzled system for adequate wound healing following myocardial infarction. Although still much has to be learned about the detailed role of the wnt-frizzled cascade in cardiovascular pathology, the nature of the system, i.e. a ligand–receptor interaction, offers potential opportunities for future therapeutic interventions.

Time for primary review 31 days.


   References
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 1. Introduction
 2. Brief outline of...
 3. The wnt-frizzled pathway...
 4. The wnt-frizzled cascade...
 5. The wnt-frizzled cascade,...
 6. The wnt-frizzled cascade...
 7. Conclusions
 References
 

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