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Cardiovascular Research 2005 65(3):587-598; doi:10.1016/j.cardiores.2004.08.016
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Copyright © 2005, European Society of Cardiology

Tyrosine phosphatases in vessel wall signaling

Kai Kapperta, Kevin G. Petersb, Frank D. Böhmerc and Arne Östmana,*

aCancer Center Karolinska, Department Of Oncology and Pathology, R8:03, Karolinska Institutet, 171 76 Stockholm, Sweden
bProcter and Gamble Pharmaceuticals, 8700 Mason Montgomery Road, Box 1064, Mason, OH 45040, USA
cInstitute of Molecular Cell Biology, Medical Faculty, Friedrich Schiller University, D-07747 Jena, Germany

* Corresponding author. Tel.: +46 8 5177 0232; fax: +46 8 33 90 31. Email address: Arne.Ostman{at}cck.ki.se

Received 24 June 2004; revised 26 August 2004; accepted 29 August 2004


   Abstract
Top
 Abstract
1. Introduction
 2. The biochemistry of...
 3. PTP activity in...
 4. PTP inhibitors for...
 5. Therapeutic opportunities...
 6. Future perspectives
 References
 
Protein tyrosine phosphatases (PTPs) are critical regulators of cellular processes like migration, proliferation and differentiation that are involved in physiological and pathological vessel wall function. In this review, we summarize the biochemistry of this enzyme family, discuss the present knowledge concerning the identity and involvement of PTPs in vascular cells and in pathways of relevance to cardiovascular diseases. We also briefly introduce ongoing efforts to develop inhibitors of PTPs, and finally point to some opportunities for use of such agents in novel treatment strategies.

KEYWORDS Protein tyrosine phosphatase; Cardiovascular disease; Cell signaling; Angiogenesis; Antherogenesis


   1. Introduction
Top
 Abstract
 1. Introduction
2. The biochemistry of...
 3. PTP activity in...
 4. PTP inhibitors for...
 5. Therapeutic opportunities...
 6. Future perspectives
 References
 
Cardiovascular disease is associated with dysregulated migration, proliferation and differentiation of cells that make up the vessel wall. A major biochemical mechanism that controls these cellular processes is reversible tyrosine phosphorylation of cell surface receptors and their intracellular mediators. Tyrosine phosphorylation is controlled by, e.g., activation of tyrosine kinase receptors, cytokine signaling involving Janus kinases, and the activation of integrins. However, the counteraction of protein tyrosine phosphatases (PTPs) is an additional important determinant of signaling. Receptor tyrosine kinases (RTKs) are already well-established mediators of pathological processes, and subject to intense investigations as drug targets. As endogenous antagonists, and in some cases also mediators, of tyrosine kinase signaling, PTPs are attracting increasing attention in many areas of biomedical research.


   2. The biochemistry of PTPs
Top
 Abstract
 1. Introduction
 2. The biochemistry of...
3. PTP activity in...
 4. PTP inhibitors for...
 5. Therapeutic opportunities...
 6. Future perspectives
 References
 
2.1. The PTP family
"Classical PTPs", hereafter referred to only as PTPs, constitute one of three subfamilies of enzymes with tyrosine phosphatase activity, the other being dual-specificity PTPs and low-molecular-weight PTPs. Thirty-eight PTPs, all sharing a catalytic signature motif V/I H C S X G, have been identified in the human genome [1]. The catalytic mechanism of PTP activity is well worked out and involves the formation of a cysteinyl-phosphate intermediate, which is followed by hydrolysis of the intermediate [2].

PTPs are divided into receptor-like PTPs (rPTPs), which span the cell membrane, and cytosolic PTPs. The extracellular domains of rPTPs show large structural variability (see Fig. 1). Most rPTPs have two tandem intracellular PTP domains. The catalytic activity resides predominatly in the first domain, whereas the second domain presumably exerts regulatory functions (see below). The cytosolic PTPs contain, in addition to the catalytic domain, sequences regulating their activity or location. Such domains include the SH2-domains of SHP-1 and SHP-2, the endoplasmatic reticulum-targeting sequence of PTP-1B and the FERM-domain of PTP-H1 (Fig. 1).


Figure 1
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  		Fig. 1 Structural diversity of PTPs. Schematic illustration of the domain structure of a selected set of rPTPs (top part) and cytosolic PTPs (lower part).

 
2.2. Regulation of PTPs
PTPs are regulated through multiple mechanisms. Phosphorylation of PTPs can enhance or decrease their activity [3–6]. Reversible oxidation of the active site cysteine residue has recently been identified as a general mechanism for regulation of PTPs [7–9]. In rPTPs, the second domain appears to be particularly sensitive to oxidation, indicating a redox sensor function of these domains and presenting an interesting ability for cross-talk between redox signaling and phosphorylation [10]. In the case of PTP-{delta}/{zeta}, an extracellular ligand, pleiotrophin, with antagonistic activity has been identified [11]. Concerning DEP-1, evidence implying the existence of agonistic extracellular ligands has been presented [12]. In the cases of PTP-µ, -{sigma} and -{delta}, homophilic interactions involving the extracellular domains have been described [13]. However, there is as yet no evidence that these homophilic interactions alter the specific activity. Finally, in the case of rPTP{alpha}, a series of studies suggest dimerization as an inhibitory regulatory mechanism [14,15].

PTP activity is also regulated through subcellular translocations such as the calpain-mediated release of PTP-1B from the endoplasmatic reticulum [16], and the SH2-domain-mediated recruitment of SHP-1 and SHP-2 to tyrosine-phosphorylated proteins (reviewed in Ref. [17]).

2.3. PTPs as antagonists, modulators and mediators of tyrosine kinase signaling
The catalytical domains of PTPs display a high degree of specificity that is achieved through extensive interactions between nonconserved residues of PTPs, and amino acids surrounding the phosphorylated tyrosine residues in substrates [18–21]. Thus, a limited set of PTPs will act on each tyrosine phosphorylated protein.

The original view of PTPs as strict negative regulators of tyrosine kinase signaling has been challenged by observations that they in some instances act as positive mediators of tyrosine kinase signaling. Prominent examples of this include PTP{alpha} which stimulates c-Src signaling, CD45 activation of T cell-receptor signaling and SHP-2 acting as a positive mediator of RTK signaling. A second set of observations that have revised the view of PTPs as simple antagonists of tyrosine kinase signaling is the demonstration that PTPs exert site-selectivity, i.e., preferentially dephosphorylate specific sites in proteins phosphorylated on multiple tyrosines [22–25] (Fig. 2A). It might thus be more accurate to consider PTPs as modulators of signaling, rather than as strict antagonists.


Figure 2
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  		Fig. 2 PTPs display site-selectivity and exert their action in restricted subcellular compartments. (A) Signaling through tyrosine kinases involves site-specific recruitment of SH2-domain-containing proteins to autophosphorylated kinases or adaptor proteins. Recent studies indicate that individual PTPs show site-selectivity and thus determine the pattern of pathways that are activated by kinases or adaptor proteins phosphorylated on multiple tyrosines. (B) The synthesis and processing of receptor tyrosine kinases proceed through the endoplasmatic reticulum and Golgi, before they reach the plasma membrane. After ligand binding, receptors are internalized and pass through endosomes before degradation or recycling. During this course of events, their phosphorylation status is regulated by spatially restricted PTPs.

 
One final aspect of PTP action, which is only beginning to be realized, is the spatial restriction of the activity of individual PTPs (Fig. 2B). This has so far most elegantly been shown in the case of PTP-1B-mediated dephosphorylation of the EGF receptor, which occurs specifically in the endoplasmatic reticulum [26].


   3. PTP activity in different cell types in the vessel wall
Top
 Abstract
 1. Introduction
 2. The biochemistry of...
 3. PTP activity in...
4. PTP inhibitors for...
 5. Therapeutic opportunities...
 6. Future perspectives
 References
 
3.1. PTP expression in the vessel wall
In addition to tissue-based characterizations, also cultured endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) have been profiled with regard to PTP expression (Table 1). As an indication of the cell type specificity of PTP expression, it should be noted that only a subset of all analyzed PTPs could be detected in either VSMCs or ECs.


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  		Table 1 Overview of PTP expression in the vessel wall and in cultured endothelial cells and vascular smooth muscle cells

 
3.2. PTP action in ECs
EC biology is critical for physiological vascular development, tissue repair and angiogenesis. Dysfunction of ECs is considered an early step and indicator in vascular disease, such as atherogenesis. ECs respond to angiogenic growth factors such as vascular endothelial growth factor (VEGF) and angiopoietins via activation of specific cell surface RTKs resulting in the formation of new vessels (angiogenesis) and the remodeling and enlargement of preexisting vessels (arteriogenesis). Because of the prominent role of VEGF and VEGF receptors (VEGFR) and the angiopoietin/Tie system in EC biology, data summarized here focus on the role of PTP action on these pathways, as well as on PTP-involvement in EC adhesion.

3.2.1. VEGF signaling and PTPs in ECs
The RTKs of the VEGFR family is expressed predominantly in ECs [27] and VEGF is known to induce cellular responses in ECs mainly through the VEGFR2. DEP-1 and PTPβ, closely related rPTPs, are both expressed in ECs with increased expression in higher cell density, which suggests a general role for these PTPs in control of cell growth [28,29]. Knockout of the DEP-1 phosphatase domain resulted in a vascular phenotype (enlarged vessels, vascular disorganization and increased EC numbers) and embryonic lethality [30]. Expression of dominant-negative DEP-1 or RNAi knockdown resulted in enhanced VEGF-induced VEGFR2 phosphorylation and increased cellular responses, supporting a DEP-1/VEGFR2 interaction [31]. Even though PTPβ was demonstrated to decrease VEGFR2-mediated phosphorylation of VE-cadherin in triple-transfected COS cells, no evidence was obtained for direct interactions between this PTP and VEGFR2 [32,33].

Interestingly, VEGFR2 activation was enhanced in VE-cadherin null ECs [31]. This most likely occurred as a consequence of a reduced recruitment of DEP-1 to VEGFRs. VE-cadherin associates with VEGFR2, suggesting that VE-cadherin recruits VEGFR2 to intercellular junctions where DEP-1 limits its activation. VEGFR2 associated with VE-cadherin via β-catenin and DEP-1 associated with p120ctn, a protein that also associates with VE-cadherin [34]. Moreover, several other phosphatases expressed in ECs have been shown to associate with cadherin/catenin complexes consistent with a role for cadherins in regulating the localization of phosphatase activity on the cell surface [32,35,36].

SHP-1 and SHP-2 have been shown to associate with the activated VEGFR2, suggesting a regulatory function in EC signaling. SHP-1 recruitment to VEGFR2 is increased by tumor necrosis factor (TNF)-{alpha}, which inhibits VEGF-mediated VEGFR2 phosphorylation, MAP kinase activation and proliferation in cultured ECs [37]. Sodium orthovanadate (NaOV) reversed the negative effects of TNF-{alpha} on these responses. Moreover, administration of a soluble TNF-{alpha} receptor resulted in increased VEGFR2 phosphorylation, which correlated with increased capillary density in a model of acute ischemia [38]. The role of SHP-2 in VEGF-dependent signaling is incompletely understood, since it associates with the activated VEGFR2, but does not appear to alter the receptor-phosphorylation [39].

Other PTPs implicated in regulation of VEGF-signaling in ECs include PTP-1B, and the nonclassical LMW-PTP [40,41]. Overexpression of LMW-PTP in ECs attenuated VEGFR2 activation and downstream signaling in ECs in vitro and resulted in inhibition of angiogenesis in explanted rat aortic rings [41]. More recently, a small molecule PTP-1B inhibitor was shown to enhance VEGF-mediated VEGFR2 activation, migration and proliferation in cultured ECs and to stimulate angiogenesis in matrigel plugs in mice [40].

3.2.2. Impact of PTP activity on Tie2 in ECs
A large body of evidence has supported the importance of angiopoietins and their endothelial RTK, Tie2, in blood vessel formation and EC survival. As with VEGFR2, SHP-2 has been shown to associate with the activated, autophosphorylated Tie2 [42]. Mutation of the SHP-2 binding site in the C-tail of Tie2 (Y1112F) resulted in enhanced autophosphorylation and activation of downstream signaling pathways [43,44], suggesting negative regulation of the activated Tie2 by recruitment of SHP-2. PTPβ, highly expressed in ECs, was also demonstrated to interact with Tie2 and to attenuate its phosphorylation in cotransfected COS-1 cells [33].

3.2.3. Other PTPs implicated in EC biology
PTPµ is expressed in the arterial endothelium and, like PTPβ and DEP-1, localized at interendothelial cell junctions [27]. Unlike other rPTPs, PTPµ may contribute to the formation of the EC junction by homophilic binding of its extracellular domain [45]. Consistent with previous studies of the PTPµ expression pattern, mice expressing LacZ under the control of the PTPµ promoter showed LacZ expression in ECs of arteries and capillaries, but not in veins or the fenestrated capillaries of the liver and spleen [46]. Although no clear vascular phenotype was reported for the PTPµ knockout, its restricted localization should encourage further studies on PTPµ involvement in EC biology.

Recently, PTPä was identified in a screen for phosphatases expressed predominantly in endothelial cells. Overexpression of PTPä negatively regulated proliferation in ECs, but not in VSMCs or fibroblasts [47]. However, a knockout of this phosphatase did not result in an obvious vascular phenotype [48].

3.2.4. PTPs involved in EC adhesion
The platelet endothelial cell adhesion molecule-1 (PECAM-1) is an adhesion receptor, predominantly localized at intercellular connections of ECs. Many of the regulatory functions of PECAM-1 depend on its tyrosine phosphorylation and subsequent recruitment of SHP-2. PECAM-1 tyrosine phosphorylation occurs reversibly in response to exposure to hydrogen peroxide, resulting in binding of SHP-2 and the colocalization of this phosphatase at cell–cell borders [49]. These findings support a role for PECAM-1 as a sensor of oxidative stress and an involvement of PTPs in control of PECAM function.

3.3. PTP action in VSMCs
VSMCs surround the endothelium in noncapillary vessels and maintain the architecture and contraction state of the vessel wall. Moreover, VSMCs play a major role in vessel pathology, such as hypertension, aneurysms and atherosclerosis.

3.3.1. PTPs interacting with PDGF signaling in VSMCs
Platelet-derived growth factor (PDGF) and PDGF receptors (PDGFR) are important for physiological repair mechanisms and in the pathogenesis of various proliferative diseases, such as restenosis and neointima formation (see review "Growth factors and atherogenesis" in this issue). VSMC proliferation and migration have successfully been blocked with different types of PDGF antagonists [50,51]. Interestingly, VSMCs from spontaneously hypertensive rats displayed a hyper-responsiveness to PDGF implying a possible role for overactive PDGF receptor signaling also in this process [52].

Using an in-gel assay approach, a total of four different PTPs could be identified interacting with the PDGFR-β: PTP-PEST, SHP-2, PTP-1B and TC-PTP [53]. A large set of studies indicate that SHP-2 acts as a positive mediator of signaling through many receptor tyrosine kinases [17]. In agreement with this, overexpression of SHP-2 is associated with enhanced PDGFR signaling and, conversely, SHP-2–/– cells display reduced PDGF responsiveness. The biochemical basis for this is still unclear. However, SHP-2-mediated inhibition of recruitment to PDGFR of RasGAP, which attenuates Ras-signaling, has been suggested as one mechanism whereby SHP-2 enhances PDGFR signaling [23,54].

Concerning PTPs acting as antagonists to PDGFR signaling, the strongest evidence is currently available for TC-PTP, a ubiquitously expressed cytosolic PTP. A comparison of PDGFR signaling in wild-type mouse embryo fibroblasts (MEFs) and TC-PTP–/– MEFs showed an enhanced PDGFR phosphorylation in TC-PTP–/– cells [24]. A more detailed analysis revealed that the PLC-{gamma} binding site, pY1021, was preferentially dephosphorylated by TC-PTP. Interestingly, analyses of downstream signaling events also indicated a preferential enhancement of the PLC-{gamma} pathway in TC-PTP–/– cells, which was paralleled by an increased migration towards PDGF. Another PTP that has been implicated as a negative regulator of PDGFR is DEP-1, which, after transfection into PDGFR-expressing cells, reduced receptor phosphorylation and attenuated cellular responses to PDGF [22,55]. An increased phosphorylation of the PDGFR-β was also demonstrated in fibroblasts from PTP-1B knockout mice [24,56]. Furthermore, a series of studies suggest that LMW-PTP, a nonclassical PTP, antagonizes PDGFR signaling, presumably by preferential dephosphorylation of the regulatory pY857 [57,58].

It should be noted that in most cases the role(s) of these PTPs in PDGFR signaling is deduced from cell types other than VSMCs. However, Seki et al. [59] demonstrated significant positive relationships between SHP-2 expression and bromodeoxyuridine uptake in VSMCs stimulated with PDGF, or insulin-like growth factor-I. Moreover, these authors showed an increase of SHP-2 expression in induced neointimal lesions in the rat aorta, suggesting a crucial role for this PTP in restenosis and atherogenesis. In addition, FAP-1 and PTP-1B were markedly up-regulated in VSMCs following vessel injury in the rat carotid [60]. Whether these PTPs target PDGFR in VSMCs remains to be determined.

3.3.2. Angiotensin II signaling and PTPs
Angiotensin II (ang II) exhibits various effects on VSMCs, including proliferation and migration, via type 1 and type 2 (AT1 and AT2) receptors. In vivo, most effects are mediated by the AT1 receptor. The AT2 receptor is highly expressed in the developing fetus, shows only low expression in the cardiovascular system in the adult, but is re-expressed in cells in the neointima [61,62]. Interestingly, ang II activates SHP-1 through the AT2 receptor, whereas ang II-dependent activation of SHP-2 is more specific for the AT1 receptor [63–65].

The functional importance of SHP-2 activation by AT1 receptors has been investigated. SHP-2 overexpression abolished ang-II-induced ERK activation, whereas expression of dominant-negative SHP-2 caused an increase in ang-II-induced phosphorylation of ERK1/2 [65]. These data thus identified SHP-2 as a negative regulator of ang II signaling through the AT1 receptor in VSMCs.

Concerning AT2 receptor signaling, activation of SHP-1 is required for the inhibitory effect of AT2 receptors on ERK activation. Transient transfection of a dominant-negative SHP-1 mutant into rat fetal VSMCs resulted in a significant decrease of the AT2 receptor-mediated inhibition of ERK phosphorylation [66].

Taken together, these data thus argue for SHP-1 and SHP-2 as regulators in ang II signaling in VSMCs. Since AT1 receptors are the predominantly expressed receptor isoform in human adult vessel tissue, the identification of SHP-2 as a negative regulator of this pathway is of potential importance for future pharmacological efforts.

3.3.3. Nitric oxide and PTPs
Nitric oxide (NO) can inhibit VSMC migration and defects in this mechanism may have pathological relevance.

NO-dependent up-regulation of SHP-2 via a cGMP-mediated pathway was necessary for NO-induced motility in differentiated cultured primary rat VSMCs, in agreement with a function of SHP-2 as a positive mediator of signaling (see Sections 2.3 and 3.3.1) [67]. NO also increased the activity of PTP-1B in VSMCs [68]. Activation of PTP-1B was required for the capacity of NO to decrease insulin-stimulated signal transduction and motility in VSMCs [68]. PTP-1B was previously identified as a negative regulator in VSMCs modulating phosphotyrosine levels in several focal adhesion proteins involved in cell motility [69]. Moreover, NO regulated cell shape, adhesion and migration by dephosphorylation of focal adhesion proteins via a mechanism that required PTP-1B activity [70]. In addition, PTP-PEST has been implicated in NO-regulated migratory responses in VSMCs [71]. NO donors increased PTP-PEST activity in VSMCs and overexpression of PTP-PEST resulted in inhibition of migration. Finally, overexpression of PTP-PEST mimicked NO-induced dephosphorylation of the adapter protein p130cas, whereas dominant-negative PTP-PEST blocked the effect of NO. Together, these findings suggest that up-regulation of PTP-PEST is a mechanism contributing to the NO-induced reduction in VSMC motility.


   4. PTP inhibitors for modulation of vascular functions
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 Abstract
 1. Introduction
 2. The biochemistry of...
 3. PTP activity in...
 4. PTP inhibitors for...
5. Therapeutic opportunities...
 6. Future perspectives
 References
 
4.1. Current state of PTP inhibitor development
Vanadium compounds are general PTP inhibitors and have been widely used to explore the involvement of PTPs in diverse cellular processes, including vascular processes (see Section 4.2). While the medical potential of PTP inhibitors was recognized early on, the suitability of PTPs as drug targets was critically questioned because of the high degree of conservation of their active sites and the lack of clear-cut data for selective cellular roles of PTPs or for the involvement of individual PTPs in disease processes. This situation changed in 1999/2000, when two studies on mice with inactivated PTP-1B gene were published [72,73]. These mice exhibited increased insulin sensitivity and reduced weight gain on a high-fat diet. The former phenotype could be attributed to increased signaling of insulin receptors, the latter to elevated leptin signaling and increased energy expenditure. No adverse effects of the PTP-1B gene knockout were reported. These studies clearly suggested PTP-1B as a potential drug target in type II diabetes and greatly spurred the search for selective PTP-1B inhibitors.

Screening and synthetic efforts in numerous companies and academic laboratories have subsequently shown that it seems indeed possible to obtain PTP-1B inhibitors from diverse compound families that exhibit submicromolar or even nanomolar potency (recently reviewed in Refs. [74–77]). Also, a high degree of specificity can be achieved, as exemplified by inhibitors that distinguish between PTP-1B and the structurally related TC-PTP by more than one order of magnitude. The generally high polarity of efficient PTP inhibitors, associated with poor cellular uptake, has been addressed by appropriate chemical modifications, for example applying prodrug strategies. Although there are yet only relatively few reports, efficacy of some selective PTP-1B inhibitors in enhancement of insulin responses has been shown in cellular models, as well as in preclinical diabetes models [78,79].

Apart from PTP-1B and diabetes, other PTPs and other disease areas have so far received comparatively little attention [75,80]. With the availability of a large repertoire of compounds, established screening platforms in the pharmaceutical industry, steadily improving knowledge of the molecular basis for structure–activity relationships, and increased knowledge of the role of individual PTPs in disease-relevant processes, this situation may soon change.

That previous research, focused on PTP-1B, could rapidly provide suitable inhibitors for application in a vascular setting is illustrated by elegant recent work from Peter Møller's group at Novo Nordisk [81]. Previously, this group had identified potent PTP-1B inhibitors from the 2-oxalaminobenzoic acid family. Structural and molecular modeling studies and comparison of the active sites of different PTPs revealed molecular interactions that form the basis for selectivity of these compounds. Based on this knowledge, other 2-oxalaminobenzoic acid derivatives have been generated which potently inhibit PTPβ, a PTP highly expressed in ECs (see Chapter 3) [81].

4.2. Effects on vascular processes by general PTP inhibition
The activity of vanadium compounds on the insulin receptor pathway led investigators to speculate that these nonselective phosphatase inhibitors could affect signaling in other settings such as the vasculature. Consistent with this possibility, vanadium compounds have been shown to enhance a variety of second messenger pathways in cultured ECs, including phospholipase D, focal adhesion kinase, PLC-{gamma}, c-Src, phosphatidyl inositol 3-kinase (PI3 kinase) and ERK/MAP kinase [40,82–86]. Vanadium compounds were also found to enhance the production of vasoactive metabolites such as prostaglandin I, NO and endothelium-derived hyperpolarizing factor [87–90]. Importantly, studies with phenylarsine oxide, a nonvanadium-containing, nonselective PTP inhibitor, are consistent with the effects of vanadium compounds on ECs [91,92]. Supporting the functional significance of these signaling effects, vanadium compounds have been shown to enhance EC survival, proliferation and capillary morphogenesis [31,40,82,86,93–95].

The hypothesis that the actions of RTKs that promote angiogenesis such as VEGFR2 and Tie2 could be enhanced by general PTP inhibition has also been tested [82]. The PTP inhibitor bis (maltolato) oxovanadium IV (BMOV) enhanced the tyrosine phosphorylation of VEGFR2 and Tie2. The enhanced activation of VEGFR2 and Tie2 correlated with augmentation of VEGF and angiopoietin 1 mediated EC survival and migration. Moreover, BMOV enhanced angiogenesis in the rat aortic ring model and augmented collateral blood flow in a rat model of peripheral vessel disease. After 4 weeks, BMOV-treated animals had significantly higher blood flows than VEGF-treated animals, indicating that modulating multiple angiogenic pathways by PTP inhibition is superior to the delivery of a single angiogenic growth factor.

Taken together, these studies suggest that PTPs negatively regulate endothelial RTK signaling and that general PTP inhibition could provide an alternative approach to improving blood flow to collateral dependent tissue. For reasons of both safety and efficacy, it is, however, likely that selective PTP inhibitors will be required for vascular applications.


   5. Therapeutic opportunities through modulation of PTP activity
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 Abstract
 1. Introduction
 2. The biochemistry of...
 3. PTP activity in...
 4. PTP inhibitors for...
 5. Therapeutic opportunities...
6. Future perspectives
 References
 
As outlined above, PTPs are important regulators of cardiovascular processes. Targeting of these enzymes for therapeutic purposes thus merits further testing.

5.1. Pro- and anti-angiogenic effects through manipulation of PTP activity
ECs, the major target cells for pro- or anti-angiogenic approaches, are controlled by the RTKs activated by VEGF, angiopoietin and fibroblast growth factor. Therefore, phosphatases involved in the regulation of these RTKs are the most obvious candidates for drug development aiming at pro- or anti-angiogenic effects (see Fig. 3). In support of the notion of PTPs as potential targets for pro- or anti-angiogenic effects, some initial studies have already demonstrated increased angiogenesis in animal models due to general PTP inhibition [40,82]. A recent example of the use of a more specific inhibitor is the application of a selective PTP-1B inhibitor, difluoro (phenyl) methylphosphonic acid-3. Incubation of ECs with this compound was capable of promoting both VEGF-dependent proliferation and migration of ECs via alteration of the PI3-kinase pathway in vitro, and angiogenesis in a matrigel plug assay in vivo [40].


Figure 3
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  		Fig. 3 Therapeutic potential of PTP activity in VSMCs and ECs. (A) Angiogenesis is a complex multistep process, involving in particular the proliferation and migration of ECs from preexisting capillaries, and maturation of vessels through recruitment of pericytes to the newly formed branches. Angiogenesis could be modulated by inhibition of PTPs acting as negative regulators in ECs or pericytes. This would result in enhanced endothelial migration or proliferation and promoting angiogenesis. Alternatively, angiogenesis could be blocked by inhibition of PTPs acting as positive regulatory enzymes. (B) The hallmark of atherogenesis is the proliferation and migration of VSMCs. An initial step of atherogenesis is believed to involve endothelial damage, resulting in endothelial dysfunction. Both cell types are therefore potentially targets for modulating PTP activity. Blocking of PTPs acting as negative regulators in ECs could lead to enhanced endothelial recovery, for instance following vascular injury. Inhibition of PTPs acting as positive regulatory enzymes in VSMCs would result in therapeutic effects through impairment of cell proliferation and migration.

 
In this context, it is also worthwhile to refer to the accumulating evidence that individual PTPs act as site-specific modulators of RTK signaling. PTP targeting can thus be associated with pathway-specific effects, resulting, e.g., in effects on EC migration without affecting proliferation, which will be difficult to achieve with RTK agonists or antagonists.

5.2. Anti-atherogenic effects of PTP-targeting drugs
Atherogenesis is a multifactorial and multicellular inflammatory disease, which involves ECs, VSMCs and inflammatory cells (reviewed in this issue: "Growth Factors in the Vascular System"). Therefore, pharmacological alterations of PTP activity in these cell types might yield therapeutic effects (see Fig. 3). EC death, resulting in vulnerable vessels, is a well-established cause of atherosclerosis and neointima formation. Protection from this event, and enhancement of re-endothelialization through activation of pro-endothelial signaling, is thus an emerging therapeutic approach [96–98]. In this context, inhibition of PTPs acting as negative regulators of VEGFRs in ECs constitutes a yet untested opportunity. As for the VSMC proliferation and migration, which are hallmarks of restenosis, PDGFR activation is an important driving force. The evidence that SHP-2 acts as a positive mediator of PDGFR signaling thus suggests that targeting this PTP could have anti-atherogenic effects.

Wright et al. [60] have also established a significant increase of the PTPs PTPL1 and PTP-1B in VSMCs following catheter-induced injury in a rat carotid model. Whether an alteration of the activity of these PTPs would result in modification of neointimal formation also remains to be determined. Moreover, Yamashita et al. [99] reported that the somatostatin analog octreotide increased phosphatase activity and reduced VSMC proliferation and migration after balloon injury.


   6. Future perspectives
Top
 Abstract
 1. Introduction
 2. The biochemistry of...
 3. PTP activity in...
 4. PTP inhibitors for...
 5. Therapeutic opportunities...
 6. Future perspectives
References
 
Apart from modulation of vascular signaling triggered by growth factors, NO, angiotensin or adhesion, there are also interesting observations of roles of PTPs in other signaling pathways, e.g., VSMC contraction [100], stretch-induced signaling in VSMCs [101] and shear-stress signaling in ECs [102,103]. These preliminary findings obviously merit further studies and are likely to expand the knowledge of the roles of PTPs in cardiovascular biology.

In this review, focus has been on ECs and VSMCs. Other cell types of obvious interest in vascular biology and disease, are pericytes and inflammatory cells. The involvement of PTPs in pericyte biology is largely unknown. PDGFR is of particular importance for pericytes, and increasing evidence suggests an important stabilizing function of pericytes in angiogenesis. The effects of inhibition of PDGFR-targeting PTPs should be investigated in models of therapeutic angiogenesis. The possibility to manipulate the function of inflammatory cells, through altering PTP actvity, is indicated by the phenotype of the naturally occurring "motheaten mice" in which SHP-1 function is attenuated and where hyperproliferation of macrophages and monocytes is a prominent phenotype [104,105].

Future development of PTPs as drug targets in the cardiovascular system will depend mostly on progress in two areas: identification of the relevant PTPs using in vivo models and development of PTP inhibitors with suitable specificity and acceptable pharmacokinetic properties. Concerning the latter issue, continued efforts in medicinal chemistry will hopefully circumvent the problem of high polarity of presently available compounds. Also, through the availability of specific inhibitors, it will be possible to find out to what extent limiting side effects will be caused by inhibition of physiological PTP action. As for target identification, genetic strategies will be extremely useful. Tissue-specific knockout of individual PTPs, used in combination with in vivo models for angiogenesis and vasculoproliferative diseases, is likely to be of critical importance for continued evaluation of the therapeutic potential of PTP inhibition in the cardiovascular system.


   Acknowledgements
 
We apologize to authors of literature which were not cited due to size constraints. K.K and F.D.B. are supported by the Deutsche Forschungsgemeinschaft (KA 1820/1-1 and BO1043-4, respectively). A.Ö. receives funding from the Swedish Cancer Society, The Swedish Research Council and Karolinska Institutet.


   Notes
 
Time for primary review 29 days


   References
Top
 Abstract
 1. Introduction
 2. The biochemistry of...
 3. PTP activity in...
 4. PTP inhibitors for...
 5. Therapeutic opportunities...
 6. Future perspectives
 References
 

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