Regulation of angiogenesis by extracellular matrix

Biochimica et Biophysica Acta 1654 (2004) 13 – 22 www.bba-direct.com

Review

Regulation of angiogenesis by extracellular matrix Jane Sottile * Center for Cardiovascular Research, Department of Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Box 679, Rochester, NY 14642, USA Received 3 April 2003; accepted 4 July 2003

Abstract During angiogenesis, endothelial cell growth, migration, and tube formation are regulated by pro- and anti-angiogenic factors, matrixdegrading proteases, and cell – extracellular matrix interactions. Temporal and spatial regulation of extracellular matrix remodeling events allows for local changes in net matrix deposition or degradation, which in turn contributes to control of cell growth, migration, and differentiation during different stages of angiogenesis. Remodeling of the extracellular matrix can have either pro- or anti-angiogenic effects. Extracellular matrix remodeling by proteases promotes cell migration, a critical event in the formation of new vessels. Matrix-bound growth factors released by proteases and/or by angiogenic factors promote angiogenesis by enhancing endothelial migration and growth. Extracellular matrix molecules, such as thrombospondin-1 and -2, and proteolytic fragments of matrix molecules, such as endostatin, can exert anti-angiogenic effects by inhibiting endothelial cell proliferation, migration and tube formation. In contrast, other matrix molecules promote endothelial cell growth and morphogenesis, and/or stabilize nascent blood vessels. Hence, extracellular matrix molecules and extracellular matrix remodelling events play a key role in regulating angiogenesis. D 2004 Elsevier B.V. All rights reserved. Keywords: Angiogenesis; Extracellular matrix; Fibronectin; Collagen; Thrombospondin; Endothelial cell

1. Introduction Much excitement has been generated by the identification of angiogenic inhibitors that block tumor growth in experimental animal models. A number of these inhibitors are currently in various stages of clinical trials [1,2]. Antiangiogenic compounds block angiogenesis by a variety of mechanisms. These inhibitors can act by inhibiting endothelial cell growth, migration, tube formation, and/or survival [3– 6]. Anti-angiogenesis factors can block endothelial cell – receptor interactions, inhibit the activity of angiogenic factors, interfere with the assembly of extracellular matrix, and/ or perturb extracellular matrix remodeling events [2,3,6 – 9]. Many reports have focused on the effects of soluble factors, such as vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF) in regulating angiogenesis [10 –16]. Less attention has been paid to the role of insoluble extracellular matrix molecules in controlling blood vessel growth. This review focuses on the myriad roles extracellular matrix molecules play in regulating endothelial cell functions that are critical for angiogenesis (see Table 1). * Tel.: +1-585-273-1532; fax: +1-585-273-1497. E-mail address: [email protected] (J. Sottile). 0304-419X/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.bbcan.2003.07.002

2. Proteolytic processing of extracellular matrix molecules Proteolytic processing of extracellular matrix molecules can have either stimulatory or inhibitory effects on angiogenesis. Extracellular matrix degradation by matrix metalloproteinases (MMPs) or plasmin can promote angiogenesis by stimulating endothelial cell migration [17 – 19]. This stimulatory effect on migration may due to decreasing the density of extracellular matrix proteins, and/or by exposing cryptic binding sites within matrix molecules that promote migration [18,20]. Proteases can also release matrix-bound angiogenic factors such as FGF-2 [21 –23]. In contrast, the action of proteases can be anti-angiogenic, due to their ability to generate fragments of matrix molecules that have antiangiogenic properties not possessed by the intact molecule [3,7,24,25]. The anti-angiogenic factor, endostatin, is a widely studied proteolytic fragment of collagen XVIII that can be generated by elastase as well as other proteases [19,24,26]. A number of other proteolytic fragments of matrix proteins have also been shown to be anti-angiogenic (summarized in Table 2). It is not known whether all of these fragments can be produced in vivo. However, their ability to inhibit various endothelial cell functions important for angiogenesis makes

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Table 1 Effect of ECM proteins on angiogenesis ECM Protein

In vitro effects

In vivo effects

Phenotypea of mouse or human mutant

References

Collagen I

Promotes ECb tube formation; induces MMP expression

Blood vessel rupture (m)c

[131,133,148,149]

Collagen III

Regulates collagen I fibril formation Promotes EC adhesion, migration; Exposure of cryptic site promotes angiogenesis C-terminal fragment inhibits EC migration

Stabilizes blood vessels; antagonists inhibit angiogenesis Stabilizes blood vessels

Blood vessel rupture (m, h)

[131,132]

C-terminal fragments block angiogenesis

NRd

[7,18,20,55,56,150]

Stabilizes microvessels; C-terminal fragment blocks angiogenesis C-terminal fragment blocks angiogenesis and tumor growth

EC degeneration and abnormal microvessels in heart and skeletal muscle (m) Abnormal retinal blood vessel formation (m); abnormal retinal structure (h) Abnormal collagen fibrils (m)

[25,53,151]

Aortic aneurysms (m, h) Predisposed to spontaneous hemorrhages (m) EC abnormalities; massive hemorrhages (m) Defective vascular development (m) NR Abnormal basement membrane assembly (m) Defective microvessel maturation; abnormal basement membrane formation (m) Decreased stability of basement membrane (m) NR Altered collagen deposition (m)

[129,154] [59,155,156,159]

Increased vascular density in skin (m) Increased vascular density in skin and other tissues (m) Decreased angiogenesis after wounding (m)

[5,40,42,173,174]

Collagen IV

Collagen XV

Collagen XVIII

Decorin

Fibrillin-1 Fibrin/Fibrinogen

C-terminal fragment (endostatin) blocks EC growth, stabilizes endothelial tubes Inhibits EC migration, tube formation; inhibits VEGF production Promotes EC tube formation, migration

Fibulin-1 Fibronectin

Laminin 8

Perlecan

Enhances FGF signalling

Tenascin C Tenascin X

Thrombospondin 2

Promotes EC migration, sprouting Binds to VEGF, enhances VEGF induced cell growth Inhibits EC growth, tube formation; promotes apoptosis Inhibits EC growth

Vitronectin

Promotes EC survival, migration

Thrombospondin 1

Stabilizes blood vessels Fragments affect angiogenesis Stabilizes blood vessels

Promotes EC adhesion, growth, survival; enhances VEGF activity Modulates FGF signalling Promotes EC tube formation; modulates endostatin activity Promotes EC morphogenesis

Glypican Laminin 1

Inhibits tumor associated angiogenesis

Antagonists block angiogenesis

Antagonist blocks angiogenesis Promotes angiogenesis

Inhibits angiogenesis Inhibits angiogenesis

[51,54,152,153,157]

[8,47,50]

[158] [58,64 – 66,90] [160 – 162] [102,163] [92,164]

[165 – 167] [168 – 170] [171,172]

[28,44,45,175] [67,176,177]

a

Phenotype relevant to angiogenesis or blood vessel maintenance. EC = endothelial cell. c m = mouse; h = human. d NR = no reported vascular phenotype. b

them potential candidates for inhibiting angiogenesis in clinical settings.

3. Anti-angiogenic effects of intact extracellular matrix molecules Extracellular matrix molecules, such as thrombospondin1 and -2, have been identified as anti-angiogenic factors [27,28]. Thrombospondin-1 was first described as a component of platelet alpha granules that is released upon platelet activation [29,30]. Subsequently, thrombospondin1 was found to be produced by a variety of cell types

including endothelial cells, smooth muscle cells, and fibroblasts [31 –34]. Thrombospondin-1 has been localized to the extracellular matrix of cells in culture, as well as tissues [34 – 36]. Thrombospondin-1 inhibits angiogenesis stimulated by FGF, and angiogenesis associated with wound healing and tumorigenesis [27,37,38]. Thrombospondin-1 is thought to inhibit angiogenesis by inducing endothelial cell apoptosis [5,39]. The role of thrombospondin-1 as an endogenous inhibitor of angiogenesis is supported by the phenotype of thrombospondin-1 null mice, which exhibit increased vascularity in the dermis and pancreatic islets [40]. The ability of the tumor suppressor, p53, to act as an anti-angiogenic factor depends upon p53-mediated down-regulation of

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Table 2 Effects of ECM fragments on angiogenesis ECM protein a

Collagen a1 (IV) Collagen a2 (IV) Collagen a3 (IV) Collagen a6 (IV) Collagen XV Collagen XVIII Fibrin Fibrinogen Fibronectin Fibronectin

Perlecan Thrombosponin-1 Thrombosponin-1 Thrombosponin-1

Fragment name

Size (kDa)

Arresten Canstatin Tumstatin

26 24 30 f25 22 20

Restin Endostatin Fragment E Fragment E III-1C (anastellin) Heparin binding fragments Endorepellin

Found in vivo

tissues tissues

50 f9 29, 40 81 140 various 70

cellsc

Effects

References

Inhibits angiogenesis; suppresses tumor growth Inhibits angiogenesis; suppresses tumor growth Inhibits angiogenesis; suppresses tumor growth Inhibits angiogenesis; suppresses tumor growth Inhibits ECb migration; suppresses tumor growth Inhibits angiogenesis; suppresses tumor growth Stimulates EC growth, migration, differentiation Disrupts vasculature; inhibits tumor growth Inhibits EC growth; inhibits tumor growth and tumor-induced angiogenesis Inhibit EC growth

[178] [56] [55] [7] [25,57] [24,26,53,57,61] [179] [59,60] [90,58]

Inhibits angiogenesis; binds endostatin Inhibits angiogenesis Inhibit angiogenesis Promotes EC tube formation and EC survival

[3] [27] [37] [182]

[180,181]

a

a1 chain of collagen IV. EC = endothelial cell. c Found in immortalized hamster cell line. b

thrombospondin-1 [41]. The ability of thrombospondin-1 to inhibit tumor growth in vivo may be transient, as evidence exists that tumors can eventually bypass the inhibitory effects of thrombospondin-1, in part, by up-regulating proangiogenic factors [46]. Thrombospondin-2 is a member of the thrombospondin gene family with a domain structure similar to thrombospondin-1 [34]. Thrombospondin-2 is present in tissue extracellular matrices, although its expression pattern during development is distinct from that of thrombospondin-1 [34]. Thrombospondin-2 inhibits endothelial cell growth [42,43], and also inhibits angiogenesis and tumor growth in vivo [28,44]. In addition, thrombospondin-2 null mice exhibit an increased vascular density in many tissues [44,45]. Another extracellular matrix molecule that has antiangiogenic properties is decorin, a proteoglycan that plays an important role in regulating collagen fibril organization [47]. Although some reports indicate that decorin promotes endothelial tube formation in collagen gels [48], other data indicate that decorin inhibits endothelial cell migration [49,50], and tube formation [50]. Further, decorin binds to thrombospondin-1 and potentiates its ability to block tube formation [50]. Tumor cells engineered to overexpress decorin show decreased growth and vascularization in vivo [8]. The ability of decorin to inhibit tumor growth and angiogenesis may be due to its ability to suppress production of VEGF [8].

4. Anti-angiogenic effects of extracellular matrix fragments Proteolytic fragments of extracellular matrix molecules as well as proteolytic fragments of blood coagulation molecules (e.g. angiostatin) [24,25,51,52] have been identified as anti-

angiogenic factors. Endostatin is a 20-kDa carboxyl-terminal fragment of collagen XVIII that has potent effects on tumor angiogenesis in animal models [24]. Details of the effects of endostatin on angiogenesis have been well documented in several recent reviews [2,6,19,53]. The striking effects of endostatin in inhibiting tumor growth in animal models [24,54] have led to its use in human clinical trial as an anticancer therapy. Although the initial results of clinical trials indicate that endostatin treatment is well tolerated by patients, significant effects in inhibiting tumor growth have yet to be demonstrated [1,2]. The non-collagenous (NC) domains of several different collagens have anti-angiogenic properties [7,25,55 – 57], even though these domains do not all have significant homology with each other. The NC-1 domains of the a2, a3, and a6 chains of collagen IV and the a1 chain of collagen XV inhibit angiogenesis and tumor growth in vivo [7,55 – 57] (summarized in Table 2). Conflicting reports exist on the ability of the a1 chain of collagen IV to inhibit angiogenesis [7,178]. Fragments of other matrix molecules, including thrombospondin-1, fibronectin, perlecan, and fibrinogen, can inhibit endothelial cell functions important for angiogenesis, and/or inhibit angiogenesis and tumor growth in vivo [3,27,58 – 60]. The precise mechanisms by which these fragments inhibit in vivo angiogenesis are not known. The importance of these fragments as endogenous regulators of angiogenesis is also unclear. The relatively large number of fragments derived from matrix and blood coagulation proteins that inhibit angiogenesis is striking. Production of these fragments may represent an important in vivo function of these proteins, apart from the better known functions of their uncleaved parent molecules. However, thus far, only a few of these matrix fragments have been found in vivo. For example, endostatin has been localized to tissues in vivo [61].

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Fibronectin fragments also exist in vivo, especially in wound fluids, and areas of inflammation [62]. Future studies will be needed to test whether these protein fragments are important endogenous regulators of angiogenesis.

5. Proangiogenic effects of extracellular matrix Many extracellular matrix molecules, including collagen, laminin, and fibronectin, promote endothelial cell survival, growth, migration, and/or tube formation, and thus have proangiogenic properties. Fibronectin affects endothelial cell adhesion, growth, migration, and survival, and is also important for in vivo angiogenesis [58,63 – 69]. Fibronectin is widely distributed in extracellular matrices throughout the body [69]. In the vasculature, fibronectin has been localized to the extracellular matrix underlying endothelial cells, and is also found in the medial and adventitial layers of the vessel wall [69 – 72]. Fibronectin is produced locally by endothelial cells and vascular smooth muscle cells, and is also present in a circulating soluble form in the plasma [69]. Soluble fibronectin is deposited into tissue extracellular matrices by a regulated, cell-dependent process [69,73 – 77]. Inhibiting fibronectin matrix deposition and/or disrupting a preexisting fibronectin matrix inhibits the growth of a number of cell types, including endothelial cells [58,78 – 80]. These and other data indicate an important role for matrix fibronectin in regulating cell growth [58,78 – 81]. Fibronectin also promotes endothelial cell survival [67,68,82] and migration [63]. In addition, fibronectin binds to VEGF and enhances VEGF-induced endothelial cell migration and MAP kinase activation [66]. Further, both fibronectin and the a5h1 fibronectin receptor are up-regulated in the vascular extracellular matrix following treatment with angiogenic factors in vivo [63]. Hence, multiple endothelial cell functions important for angiogenesis are regulated by soluble fibronectin and/or by extracellular matrix fibronectin. A number of recent studies have shown that the multimeric extracellular matrix form of fibronectin has properties distinct from soluble, protomeric fibronectin [78,81,83– 85]. Further, ongoing fibronectin matrix polymerization is important for regulating cell proliferation, cell migration, and extracellular matrix remodelling [58,79,80,85– 89]. Agents that inhibit fibronectin matrix deposition also block the deposition and retention of other protein in the extracellular matrix, including thrombospondin-1 [86]. Hence, in addition to directly regulating endothelial cell function, fibronectin may also regulate angiogenesis by controlling extracellular matrix remodelling events. Multimeric fibronectin produced in vitro has been shown to inhibit cell migration, enhance cell adhesion, inhibit tumor growth, and inhibit tumor associated angiogenesis [83,90]. Hence, the effects of fibronectin on endothelial cell function are likely to depend on the local concentration of soluble fibronectin as well as the density of the fibronectin matrix. The importance of fibronectin in the vasculature is underscored by the ability of fibronectin to

regulate in vivo angiogenesis in an animal model [63], and by the phenotype of mice lacking fibronectin [64,65,91]. Fibronectin-null mice die during embryogenesis with defects in blood vessel development and/or maintenance [64,65]. Many other matrix molecules also promote endothelial cell adhesion and survival, including laminin, various collagens, and vitronectin. Laminin 8 is the predominant laminin found in vascular basement membranes, and is likely to be the only laminin present in capillary basement membranes during embryonic development, and in neonates [92]. Mice lacking the a4 chain of laminin, which is necessary for expression of laminin 8, show impaired microvessel maturation [92]. This effect could be due to defective capillary basement membrane assembly, as collagen IV and nidogen deposition are disrupted in the absence of laminin 8 [92]. Collagen IV has also been shown to regulate angiogenesis. MMP cleavage of collagen IV exposes a cryptic epitope within collagen IV, whose presence is required for angiogenesis and tumor growth in vivo [18,20]. Earlier studies also indicate an important role for collagen synthesis and/or deposition in angiogenesis, as inhibitors of collagen cross-linking or synthesis are effective inhibitors of angiogenesis [93,94].

6. Sequestering of angiogenic and anti-angiogenic factors The extracellular matrix also affects angiogenesis by sequestering angiogenic factors, such as FGF-2 and heparin-binding forms of VEGF. Although FGF-2 is not required for angiogenesis [95], FGF-2 promotes angiogenesis in a number of animal models [5,23,37,96], stimulates endothelial proliferation and migration [97], and acts synergistically with VEGF to promote angiogenesis in vivo [12]. Matrixbound FGF-2 can be released by proteolysis [22,23]. Certain heparin-binding isoforms of VEGF can also release matrixbound FGF-2 [21], suggesting that some of the biological effects of VEGF may be mediated by FGF-2 [21]. FGF-2 also induces VEGF expression by endothelial cells [10]. VEGF is an important stimulator of angiogenesis during development [11,98], and has a variety of effects on endothelial cells, triggering endothelial cell proliferation, migration, survival and tube formation [12,17]. Several heparinbinding isoforms of VEGF exist [99 –101]. These isoforms can be localized to extracellular matrix, where they presumably bind to heparan sulfate proteoglycans [101]. The heparan sulfate proteogycan glypican-1 binds to VEGF-165 [100]. Heparin-binding VEGF that is associated with the matrix is biologically active [101]. Binding of VEGF to glypican-1 can restore receptor binding activity to oxidized VEGF, suggesting that glypican-1 may be an important regulator of VEGF activity [100]. Heparin-binding isoforms of VEGF have a unique role that cannot be replaced by nonheparin-binding isoforms, since mice engineered to lack heparin-binding VEGF show reduced microvascular development in the lung [99].

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Anti-angiogenic factors can also be associated with the extracellular matrix. Thrombospondin-1 can localize to extracellular matrices in vitro and in vivo [34 – 36]. As discussed below, the association of thrombospondin-1 with the extracellular matrix may be transitory and an important control point in regulating thrombospondin bioavailability. Endostatin has been localized to tissues in vivo [61], and can bind a number of extracellular matrix molecules, including heparan sulfate proteoglycans (glypican), fibulin, and laminin [57,102,103]. Evidence exists that some extracellular matrix molecules can modulate endostatin activity. For example, laminin blocks the ability of endostatin to inhibit endothelial cell tube formation [102]. Glypican-1 is also important for endostatin activity, as down-regulation of glypican levels in endothelial cells blocks the ability of endostatin to inhibit endothelial cell migration [103].

[64,65]. Endothelial cell differentiation, migration, and tube formation all occur in the absence of fibronectin; however, formation and/or maintenance of the vessel lumen requires fibronectin [65]. In addition, mice lacking fibronectin-binding integrins a5, a4 and av have vascular defects [126 – 128]. Collagen I, collagen III, and fibrillin also contribute to vessel wall stability, as mutations in these molecules can lead to blood vessel rupture [129 – 133]. In later stages of angiogenesis, pericytes and smooth muscle cells migrate to the sites of developing vessels, and stabilize the vessel wall, in part by production of extracellular matrix molecules [17,134]. Mice that lack angiopoietin-1, or the angiopoietin-1 receptor, TIE-2, die during embryogenesis due to vascular abnormalities that are thought to arise due to impaired interaction of endothelial cells with extracellular matrix and mesenchyme [15].

7. Extracellular matrix remodeling and angiogenesis

9. Summary

It is likely that thrombospondin-1 and -2 are transient components of the extracellular matrix, since they are both internalized by receptor-mediated endocytosis and degraded in the lysosomes in fibroblasts, endothelial cells, and smooth muscle cells [35,104 – 106]. Thrombospondin-1 binds to extracellular matrix molecules including fibronectin, fibrinogen, and heparan sulfate proteoglycans [107 – 109]. Thrombospondin-1 colocalizes with fibronectin in extracellular matrix fibrils [86]. In addition, the maintenance of fibrillar thrombospondin in the extracellular matrix depends upon the polymerization of a fibronectin matrix [86]. Turnover of matrix fibronectin leads to a corresponding disruption and loss of fibrillar thrombospondin [86]. Inhibiting fibronectin matrix deposition also inhibits collagen-I and collagen-III matrix deposition [86,110], and results in loss of preexisting collagen-I fibrils [86]. Hence, agents that regulate the rate and extent of fibronectin matrix polymerization [73,80,111 – 115] may play an important role in regulating the composition and stability of the extracellular matrix, and in regulating endothelial cell functions that are critical for angiogenesis. Proteases and protease inhibitors are also crucial factors that regulate extracellular matrix remodeling. Such remodeling could affect angiogenesis by changing the bioavailability of matrix-sequestered angiogenic or anti-angiogenic factors, by changing the composition and organization of the matrix, and/or by exposing cryptic epitopes within matrix molecules [18,20,22,23,116– 119]. Many excellent reviews discuss this topic in more detail [19,120 – 125].

Cells must integrate information from myriad growth factors, cytokines, and matrix molecules before becoming committed to a proliferative, migratory, or differentiation pathway. It is likely that the precise composition of matrix molecules, as well as of soluble angiogenic and antiangiogenic factors, is spatially and temporally regulated during angiogenesis, and that the balance between these factors is a key determinant in triggering specific cell behaviors. Many studies that have tested the effects of pro- and anti-angiogenic factors have optimized the concentrations and delivery of these agents. In vivo, the situation is likely to involve a more complex mixture of stimulatory and inhibitory molecules that may or may not be present at optimal concentrations. Many studies have shown that endothelial cell survival depends upon cell –extracellular matrix interactions. Integrins play an important role in mediating cell adhesion and survival [135 –137]. In an elegant series of experiments it has been shown that modulating the concentration and patterning of matrix proteins results in a spectrum of cell spreading which leads to cell responses ranging from apoptosis, to growth, to differentiation [138]. Similarly, the migratory response of cells to extracellular matrix is biphasic. High or low concentrations of matrix proteins are suboptimal for cell migration, while intermediate concentrations promote optimal migration [87,139,140]. In addition, cell –extracellular matrix interactions are required for the mitogenic response of cells to soluble growth factors [141 –144]. However, simple integrin ligation to extracellular matrix does not explain all cell responses to extracellular matrix. A number of studies have shown that cells can sense the three-dimensional organization of fibrillar extracellular matrix proteins, and that cell phenotype can be altered by changing the composition and/or organization of matrix fibrils [81,89,145]. One way in which cells may distinguish between fibrillar matrix proteins and unpolymerized pro-

8. Blood vessel stability Extracellular matrix molecules also play an important role in stabilizing blood vessels. Mice lacking fibronectin die during embryogenesis due to cardiovascular defects

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teins is through the exposure of cryptic epitopes within fibrillar proteins which are not present in protomeric proteins [18,20,87,88,115,116,146,147]. These cryptic epitopes could be exposed by local protease cleavage, or by conformational changes in the protein that accompany its deposition into the matrix. A full understanding of how extracellular matrix proteins influence endothelial cell behaviors that are important for angiogenesis will necessitate further insights into how extracellular matrices are assembled, what regulates the local composition and organization of the matrix, and how complex combinations of matrix molecules influence cell fate.

Acknowledgements The author thanks Dr. Denise Hocking (University of Rochester) for critically reading this review. Work on fibronectin in the author’s laboratory is supported by grants HL03971 from the National Institutes of Health and 0250282N from the American Heart Association.

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