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• W2016576487 abstract "SummaryVascular development requires correct interactions among endothelial cells, pericytes and surrounding cells. These interactions involve many cell adhesion interactions, including cell–matrix interactions both with basement membranes and with surrounding extracellular matrices. Investigations of the contributions of these various interactions in vascular development and angiogenesis have been rather uneven and incomplete over the past 10–15 years. There has been considerable concentration on a few receptors, matrix proteins and proteolytic fragments with the goal of finding means to control angiogenesis. Many other potential contributors have received much less attention. Even for those molecules that have been subject to intensive investigation, our knowledge is incomplete. This review will survey the spectrum of extracellular matrix (ECM) proteins and cell–matrix adhesion receptors (particularly integrins) that are likely to contribute to angiogenesis and discuss what is known and not known about the roles of each of them. Vascular development requires correct interactions among endothelial cells, pericytes and surrounding cells. These interactions involve many cell adhesion interactions, including cell–matrix interactions both with basement membranes and with surrounding extracellular matrices. Investigations of the contributions of these various interactions in vascular development and angiogenesis have been rather uneven and incomplete over the past 10–15 years. There has been considerable concentration on a few receptors, matrix proteins and proteolytic fragments with the goal of finding means to control angiogenesis. Many other potential contributors have received much less attention. Even for those molecules that have been subject to intensive investigation, our knowledge is incomplete. This review will survey the spectrum of extracellular matrix (ECM) proteins and cell–matrix adhesion receptors (particularly integrins) that are likely to contribute to angiogenesis and discuss what is known and not known about the roles of each of them. Vascular development is a complex multi-step process, involving multiple cell types that must interact with one another and with the surrounding cells and extracellular matrix. In addition to the need for endothelial cells to associate with each other and form tubular structures, processes involving cell migration and both cell–cell and cell–matrix adhesion, they must also attract pericytes to surround the endothelial tube and form a joint basement membrane between and around them. Furthermore, correct vascular organization requires interactions of the basic vascular unit (endothelium–pericytes-basement membrane) with the surrounding cells. One example of the importance of this outer layer of cellular interactions for vascular integrity comes from study of the defects in cerebral vasculature in mice lacking αv integrins [1Bader B.L. Rayburn H. Crowley D. Hynes R.O. Extensive vasculogenesis, angiogenesis and organogenesis precede lethality in mice lacking all αv integrins.Cell. 1998; 95: 507-19Abstract Full Text Full Text PDF PubMed Scopus (543) Google Scholar, 2McCarty J.H. Monahan-Earley R.A. Dvorak A.M. Brown L.F. Keller M. Gerhardt H. Rubin K. Shani M. Wolburg H. Bader B.L. Dvorak H.F. Hynes R.O. Defective associations between blood vessels and developing neuronal parenchyma lead to cerebral hemorrhage in mice lacking αv integrins.Mol Cell Bio. 2002; 22: 7667-77Crossref PubMed Scopus (141) Google Scholar, 3McCarty J.H. Lacy-Hulbert A. Charest A. Bronson R.T. Crowley D. Housman D.H. Savill J. Hynes R.O. Selective ablation of αv integrins in the central nervous system leads to cerebral hemorrhage, seizures, axonal degeneration and premature death.Development. 2005; 132: 165-76Crossref PubMed Scopus (186) Google Scholar]. Although initial results suggested that this defect might arise as a consequence of loss of αv integrins from endothelial cells and/or from pericytes, it turned out on further analysis that the defect lay in the absence of αvβ8 integrin from astrocyte endfeet; this absence interfered with apposition of the glia with the invading vessels and led to vessel dilation and eventual rupture [2McCarty J.H. Monahan-Earley R.A. Dvorak A.M. Brown L.F. Keller M. Gerhardt H. Rubin K. Shani M. Wolburg H. Bader B.L. Dvorak H.F. Hynes R.O. Defective associations between blood vessels and developing neuronal parenchyma lead to cerebral hemorrhage in mice lacking αv integrins.Mol Cell Bio. 2002; 22: 7667-77Crossref PubMed Scopus (141) Google Scholar, 3McCarty J.H. Lacy-Hulbert A. Charest A. Bronson R.T. Crowley D. Housman D.H. Savill J. Hynes R.O. Selective ablation of αv integrins in the central nervous system leads to cerebral hemorrhage, seizures, axonal degeneration and premature death.Development. 2005; 132: 165-76Crossref PubMed Scopus (186) Google Scholar]. This example illustrates the need for recognition of the complexity of the intercellular interactions necessary for building and maintaining a properly formed vasculature. In this review we will be concerned with cell–matrix adhesions contributing to these processes. Although a considerable amount of research has been devoted to this topic, we are still far from understanding the functions of the multiple matrix proteins and cell–matrix receptors and, in what follows, I will attempt to point out where further research is needed. Given the availability of genomic sequences, we have a reasonably good ‘parts list’ of the potential matrix proteins and receptors but attention has focused on a few of them at the expense of a systematic analysis. There has been a strong focus on endothelial cells, with less attention paid to pericytes and very little to the parenchymal cells surrounding the vessels. There has also been an emphasis on in vitro models of angiogenesis and there is need for a more comprehensive analysis of in vivo models using the power of mouse genetics, again with attention to the individual cell types involved, a problem now accessible using cell-type-specific mutation of genes of interest. I concentrate on areas in which we have ourselves expended most effort [fibronectin (FN) and its receptors and the αv integrins] but survey results on other matrix proteins and integrins and note where more research would be valuable. Interactions of vascular wall cells (endothelial cells and pericytes) with extracellular matrix involve diverse extracellular matrix molecules, which differ to some degree among vessels and certainly differ depending on the state of the vessel (quiescent, injured or angiogenic) [4Davis G.E. Senger D.R. Endothelial extracellular matrix: biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization.Circ Res. 2005; 97: 1093-107Crossref PubMed Scopus (934) Google Scholar]. In resting vessels, endothelial cells are in contact with a basement membrane, which they share with pericytes in the case of small vessels. Vascular basement membranes contain laminins (predominantly laminin-8/ laminin411 and laminin-10/ laminin511), type IV collagens, perlecan, nidogens, collagen XVIII and von Willebrand factor. The endothelial cells and pericytes in mature, quiescent vessels are non-proliferative and stably attached to the basement membrane. During vascular remodeling and angiogenesis, it is generally believed that the quiescent endothelial layer becomes ‘activated’ and endothelial cells breach the basement membrane and migrate into surrounding tissue containing different complements of extracellular matrix proteins, which can include collagens and FNs in interstitial extracellular matrix or fibrinogen and FNs in provisional matrices generated after vascular injury and during wound healing. Similarly, the extracellular matrices of tumors also contain fibrinogen and FNs. Other extracellular matrix (ECM) proteins encountered by endothelial cells and pericytes include vitronectin, thrombopondins and tenascins. The effects of ECM on vascular wall cells therefore differ greatly, depending on the state of the vessel and, very probably, to a lesser degree among different vessels. It is evident that the switch from quiescence (adherent to laminins and probably other basement membrane proteins, stably assembled into tubes) to the angiogenic state (migratory, invasive, tube remodeling and formation) involves marked changes in the cell–matrix interactions in which the cells are involved. It is also evident that different sorts of angiogenesis probably involve different forms of ECM and therefore different cell–matrix interactions. This is undoubtedly one reason why there is, as yet, no all-encompassing hypothesis concerning the cell–matrix adhesions that are important for angiogenesis; the likelihood is that there are multiple such interactions that differ in the course of a single angiogenic process and between angiogenesis in different situations (e.g. embryonic, retinal, tumor or wound healing angiogenesis). Knockout mice lacking many of the basement membrane proteins listed above have been generated. By and large, they have not lent much support to hypotheses implicating those proteins in vascular development [4Davis G.E. Senger D.R. Endothelial extracellular matrix: biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization.Circ Res. 2005; 97: 1093-107Crossref PubMed Scopus (934) Google Scholar, 5Hynes R.O. Bader B.L. Targeted mutations in integrins and their ligands: their implications for vascular biology.Thromb Haemost. 1997; 78: 83-7Crossref PubMed Scopus (58) Google Scholar, 6Hynes R.O. Lively J.C. McCarty J.H. Taverna D. Francis S.E. Hodivala-Dilke K. Xiao Q. Diverse roles of integrins and their ligands in angiogenesis.Cold Spring Harbor Symp Quant Biol. 2002; 67: 143-53Crossref PubMed Scopus (104) Google Scholar], although in many cases, only developmental angiogenesis has been assessed and further research could, yet, reveal more subtle defects. Examples of knockouts showing no obvious defects in angiogenesis include nidogens, perlecan, vitronectin, and von Willebrand factor. The absence of any obvious angiogenic defects could, of course, arise from the existence of overlapping functions among related (or even unrelated) proteins or from compensation in response to the ablation of a given gene. These two different phenomena (overlapping function and compensation) are frequently lumped together under the rubric of ‘redundancy’ but this usage is not helpful and it is instructive to keep the two concepts distinct; one is a consequence of a natural overlap in the functions of two genes in a given process, the other is a response to perturbation in response to a mutation – it may or may not be informative of a natural compensatory effect. In either event, the failure to observe an angiogenic defect does not rule out a role for the gene in question; it does, however, show clearly that the gene is not essential. In contrast, a defect in vascular development as a consequence of deletion of a given gene provides strong justification for inferring a role, as is the case for FNs and thrombospondins. Mutation of FNs or their receptors leads to clear vascular and angiogenic defects during embryonic development [1Bader B.L. Rayburn H. Crowley D. Hynes R.O. Extensive vasculogenesis, angiogenesis and organogenesis precede lethality in mice lacking all αv integrins.Cell. 1998; 95: 507-19Abstract Full Text Full Text PDF PubMed Scopus (543) Google Scholar, 7George E.L. Georges-Labouesse E.N. Patel-King R.S. Rayburn H. Hynes R.O. Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin.Development. 1993; 119: 1079-91Crossref PubMed Google Scholar, 8Georges-Labouesse E.N. George E.L. Rayburn H. Hynes R.O. Mesodermal development in mouse embryos mutant for fibronectin.Dev Dyn. 1996; 207: 145-56Crossref PubMed Scopus (137) Google Scholar, 9George E.L. Baldwin H.S. Hynes R.O. Fibronectins are essential for heart and blood vessel morphogenesis but are dispensable for initial specification of precursor cells.Blood. 1997; 90: 3073-81Crossref PubMed Google Scholar, 10Yang J.T. Rayburn H. Hynes R.O. Embryonic mesodermal defects in α5-integrin-deficient mice.Development. 1993; 119: 1093-105Crossref PubMed Google Scholar, 11Goh K.L. Yang J.T. Hynes R.O. Mesodermal defects and cranial neural crest apoptosis in α5 integrin-null embryos.Development. 1997; 124: 4309-19Crossref PubMed Google Scholar, 12Francis S.E. Goh K.L. Hodivala-Dilke K. Bader B.L. Stark M. Davidson D. Hynes R.O. Central roles of α5β1 integrin and fibronectin in vascular development in mouse embryos and embryoid bodies.Arterioscler Thromb Vasc Biol. 2002; 22: 927-33Crossref PubMed Scopus (237) Google Scholar, 13Yang J.T. Rayburn H. Hynes R.O. Cell adhesion events mediated by α4 integrins are essential in placental and cardiac development.Development. 1995; 121: 549-60Crossref PubMed Google Scholar, 14Yang J.T. Bader B.L. Kreidberg J.A. Ullman-Culleré M. Trevithick J.E. Hynes R.O. Overlapping and independent functions of fibronectin receptor integrins in early mesodermal development.Devel Biol. 1999; 215: 264-77Crossref PubMed Scopus (122) Google Scholar]. In contrast, deletion of thrombospondins produces little in the way of defects in vascular development but does implicate these proteins as endogenous inhibitors of angiogenesis [15Lawler J. Sunday M. Thibert V. Duquette M. George E.L. Rayburn H. Hynes R.O. Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia.J Clin Invest. 1998; 101: 982-92Crossref PubMed Scopus (384) Google Scholar, 16Kyriakides T.R. Zhu Y.H. Smith L.T. Bain S.D. Yang Z. Lin M.T. Danielson K.G. Iozzo R.V. LaMarca M. McKinney C.E. Ginns E.I. Bornstein P. Mice that lack thrombospondin 2 display connective tissue abnormalities that are associated with disordered collagen fibrillogenesis, an increased vascular density, and a bleeding diathesis.J Cell Biol. 1998; 140: 419-30Crossref PubMed Scopus (405) Google Scholar, 17Streit M. Riccardi L. Velasco P. Brown L.F. Hawighorst T. Bornstein P. Detmar M. Thrombospondin-2: a potent endogenous inhibitor of tumor growth and angiogenesis.Proc Natl Acad Sci USA. 1999; 96: 14888-93Crossref PubMed Scopus (253) Google Scholar, 18Streit M. Velasco P. Brown L.F. Skobe M. Richard L. Riccardi L. Lawler J. Detmar M. Overexpression of thrombospondin-1 decreases angiogenesis and inhibits the growth of human cutaneous squamous cell carcinomas.Am J Pathol. 1999; 155: 441-52Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar, 19Rodriguez-Manzaneque J.C. Lane T.F. Ortega M.A. Hynes R.O. Lawler J. Iruela-Arispe M.L. Thrombospondin-1 suppresses spontaneous tumor growth and angiogenesis and inhibits activation of matrix metalloprotease-9 and mobilisation of VEGF.Proc Natl Acad Sci USA. 2001; 98: 12485-90Crossref PubMed Scopus (386) Google Scholar, 20Agah A. Kyriakides T.R. Lawler J. Bornstein P. The lack of thrombospondin-1 (TSP1) dictates the course of wound healing in double-TSP1/TSP2-null mice.Am J Pathol. 2002; 161: 831-9Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 21Lawler J. Detmar M. Tumor progression: the effects of thrombospondin-1 and -2.Int J Biochem Cell Biol. 2004; 36: 1038-45Crossref PubMed Scopus (184) Google Scholar, 22Armstrong L.C. Bornstein P. Thrombospondins 1 and 2 function as inhibitors of angiogenesis.Matrix Biol. 2003; 22: 63-71Crossref PubMed Scopus (249) Google Scholar]. We will return to discussions of FNs and thrombospondins in later sections. Each of the many ECM proteins of vascular basement membranes or in the ECM during angiogenic sprouting has cell surface receptors, predominantly of the integrin family, although other ECM receptors (e.g. dystroglycan, GPIb, GPVI, DDR collagen receptors) are also known. In this brief review, I concentrate on integrins for lack of space and because they have been the most intensively investigated but these other possible matrix receptors should not be ignored in future research; a thorough inventory of the cell–matrix adhesion receptors on endothelial cells and pericytes of different types and in different states would be very useful. Among the integrins, nine (α1β1, α2β1, α3β1, α4β1, α5β1, α6β1, α6β4, αvβ3, αvβ5) have been implicated to one degree or another in angiogenesis 23Hynes R.O. Bader B.L. Hodivala-Dilke K. Integrins in vascular development.Braz J Med Biol Res. 1999; 32: 501-10Crossref PubMed Scopus (106) Google Scholar, 24Hynes R.O. Integrins: bi-directional, allosteric, signaling machines.Cell. 2002; 110: 673-87Abstract Full Text Full Text PDF PubMed Scopus (6844) Google Scholar, 25Hynes R.O. A reevaluation of integrins as regulators of angiogenesis.Nat Med. 2002; 8: 918-21Crossref PubMed Scopus (487) Google Scholar, 26McCarty J.H. Hynes R.O. Integrins and formation of the microvasculature.in: Shepro D Encyclopedia of the Microvasculature. Elsevier Academic Press, 2006: 335-9Google Scholar, 27McCarty J.H. Hynes R.O. Endothelial cell integrins.in: William CA The Endothelium: A Comprehensive Reference. Cambridge University Press, 2006: 697-702Google Scholar, 28Mettouchi A. Meneguzzi G. Distinct roles of beta1 integrins during angiogenesis.Eur J Cell Biol. 2006; 85: 243-7Crossref PubMed Scopus (41) Google Scholar, 29Serini G. Valdembri D. Bussolino F. Integrins and angiogenesis: a sticky business.Exp Cell Res. 2006; 312: 651-8Crossref PubMed Scopus (169) Google Scholar (Fig. 1). These include collagen receptors (α1β1, α2β1), laminin receptors ( α3β1, α6β1, α6β4), FN receptors (α4β1, α5β1) and the pair of αv receptors (αvβ3, αvβ5), which have received the most attention (see below). Each of these receptors has been described on endothelial cells (with much less information available about their expression on pericytes), although it must be noted that it should not be assumed that all endothelial cells express the same set of integrins; indeed, it is clear that many are regulated during angiogenesis. It might be expected, based on the discussion above, that the laminin receptors would play their most prominent role in quiescent vessels. However, there is good evidence that α6β4 plays a role in sprouting angiogenesis [30Nikolopoulos S.N. Blaikie P. Yoshioka T. Guo W. Giancotti F.G. Integrin beta4 signaling promotes tumor angiogenesis.Cancer Cell. 2004; 6: 471-83Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar], consistent with evidence that this integrin plays a role in the migration of epithelial cells. Similarly, some results implicate α3β1-laminin 411 interactions in angiogenesis [31Gonzalez A.M. Gonzales M. Herron G.S. Nagavarapu U. Hopkinson S.B. Tsuruta D. Jones J.C. Complex interactions between the laminin alpha 4 subunit and integrins regulate endothelial cell behavior in vitro and angiogenesis in vivo.Proc Natl Acad Sci USA. 2002; 99: 16075-80Crossref PubMed Scopus (107) Google Scholar] and the tetraspanin CD151, a close partner of α3β1, has been reported to play a role in angiogenesis [32Takeda Y. Kazarov A.R. Butterfield C.E. Hopkins B.D. Benjamin L.E. Kaipainen A. Hemler M.E. Deletion of tetraspanin Cd151 results in decreased pathologic angiogenesis in vivo and in vitro.Blood. 2007; 109: 1524-32Crossref PubMed Scopus (135) Google Scholar], supporting the idea that α3β1 may also. Vascular endothelial growth factor (VEGF) up-regulates α6β1 and antibodies and siRNA treatments directed against α6β1 inhibit angiogenesis in vivo and endothelial functions in vitro [33Lee T.H. Seng S. Li H. Kennel S.J. Avraham H.K. Avraham S. Integrin regulation by vascular endothelial growth factor in human brain microvascular endothelial cells: role of alpha6beta1 integrin in angiogenesis.J Biol Chem. 2006; 281: 40450-60Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar]. Mice deficient in either α3β1 or α6β1 show no obvious deficits in developmental angiogenesis but they have not been extensively tested for other forms of angiogenesis; as we see below, different results can often be observed depending on exactly which angiogenic response is investigated. Several lines of evidence implicate the collagen receptors, α1β1 and α2β1, in angiogenesis. They are up-regulated by angiogenic growth factors [34Senger D.R. Claffey K.P. Benes J.E. Perruzzi C.A. Sergiou A.P. Detmar M. Angiogenesis promoted by vascular endothelial growth factor: regulation through alpha1beta1 and alpha2beta1 integrins.Proc Natl Acad Sci USA. 1997; 94: 13612-7Crossref PubMed Scopus (457) Google Scholar, 35Hong Y.K. Lange-Asschenfeldt B. Velasco P. Hirakawa S. Kunstfeld R. Brown L.F. Bohlen P. Senger D.R. Detmar M. VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1beta1 and alpha2beta1 integrins.FASEB J. 2004; 18: 1111-3Crossref PubMed Scopus (256) Google Scholar] and function-blocking antibodies inhibit angiogenesis in several in vivo models [36Senger D.R. Perruzzi C.A. Streit M. Koteliansky V.E. De Fougerolles A.R. Detmar M. The alpha(1)beta(1) and alpha(2)beta(1) integrins provide critical support for vascular endothelial growth factor signaling, endothelial cell migration, and tumor angiogenesis.Am J Pathol. 2002; 160: 195-204Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar]. Furthermore, mice deficient in α1β1 show compromised tumor angiogenesis, apparently as a consequence of increased levels/activity of matrix metalloproteinases cleaving plasminogen to angiostatin, an inhibitor of angiogenesis [37Pozzi A. Moberg P.E. Miles L.A. Wagner S. Soloway P. Gardner H.A. Elevated matrix metalloprotease and angiostatin levels in integrin alpha 1 knockout mice cause reduced tumor vascularization.Proc Natl Acad Sci USA. 2000; 97: 2202-7Crossref PubMed Scopus (349) Google Scholar]. Mice deficient in α2β1 show no obvious defects in developmental angiogenesis [38Chen J. Diacovo T.G. Grenache D.G. Santoro S.A. Zutter M.M. The alpha(2) integrin subunit-deficient mouse: a multifaceted phenotype including defects of branching morphogenesis and hemostasis.Am J Pathol. 2002; 161: 337-44Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar]. Clearly, α1β1 and α2β1 could have overlapping or compensatory roles in angiogenesis but mice doubly deficient in both these integrins have yet to be studied. Thus, despite the fact that the laminin and collagen receptor integrins have not been investigated as extensively as have FN receptors and αv integrins (see below), it seems clear that they do participate and more intensive study of their roles and those of their ligands should prove productive. As with any developmental or homeostatic process, angiogenesis must be subject to negative feedback limiting its extent and, a priori, one would expect the presence of endogenous angiogenic inhibitors. There is also considerable interest in discovery and development of inhibitors of angiogenesis for use in therapy of cancer, retinal angiogenesis, etc. [39Folkman J. Antiangiogenesis in cancer therapy – endostatin and its mechanisms of action.Exp Cell Res. 2006; 312: 594-607Crossref PubMed Scopus (592) Google Scholar, 40Nyberg P. Xie L. Kalluri R. Endogenous inhibitors of angiogenesis.Cancer Res. 2005; 65: 3967-79Crossref PubMed Scopus (469) Google Scholar, 41Bix G. Iozzo R.V. Matrix revolutions: “tails” of basement-membrane components with angiostatic functions.Trends Cell Biol. 2005; 15: 52-60Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 42Sund M. Hamano Y. Sugimoto H. Sudhakar A. Soubasakos M. Yerramalla U. Benjamin L.E. Lawler J. Kieran M. Shah A. Kalluri R. Function of endogenous inhibitors of angiogenesis as endothelium-specific tumor suppressors.Proc Natl Acad Sci USA. 2005; 102: 2934-9Crossref PubMed Scopus (170) Google Scholar]. Several ECM proteins or fragments thereof have been implicated as negative regulators of angiogenesis [40Nyberg P. Xie L. Kalluri R. Endogenous inhibitors of angiogenesis.Cancer Res. 2005; 65: 3967-79Crossref PubMed Scopus (469) Google Scholar, 41Bix G. Iozzo R.V. Matrix revolutions: “tails” of basement-membrane components with angiostatic functions.Trends Cell Biol. 2005; 15: 52-60Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 42Sund M. Hamano Y. Sugimoto H. Sudhakar A. Soubasakos M. Yerramalla U. Benjamin L.E. Lawler J. Kieran M. Shah A. Kalluri R. Function of endogenous inhibitors of angiogenesis as endothelium-specific tumor suppressors.Proc Natl Acad Sci USA. 2005; 102: 2934-9Crossref PubMed Scopus (170) Google Scholar]. Some of these proposed ECM-derived angiogenic inhibitors are better validated than others (Table 1).Table 1Candidate ECM-derived inhibitors of angiogenesisProposed inhibitorSourceInhibition of EC functions in vitroInhibition of angiogenesis in vivoGenetic ablation blocks antiangiogenic effects in vivoProposed receptorDependence on receptor shown in vitroDependence on receptor shown in vivoThrombospondins TSP-1/TSP-2+++CD36EndostatinCollagen α(XVIII)+++α5β1 integrin?ArrestenCollagen α1(IV)+++α1β1 integrin+KOCanstatinCollagen α2(IV)++TumstatinCollagen α3(IV)+++αvβ3 integrin+KOEndorepellinPerlecan++AnastellinFibronectin++FibronectinKO Open table in a new tab The best established are thrombospondins 1 and 2 [15Lawler J. Sunday M. Thibert V. Duquette M. George E.L. Rayburn H. Hynes R.O. Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia.J Clin Invest. 1998; 101: 982-92Crossref PubMed Scopus (384) Google Scholar, 16Kyriakides T.R. Zhu Y.H. Smith L.T. Bain S.D. Yang Z. Lin M.T. Danielson K.G. Iozzo R.V. LaMarca M. McKinney C.E. Ginns E.I. Bornstein P. Mice that lack thrombospondin 2 display connective tissue abnormalities that are associated with disordered collagen fibrillogenesis, an increased vascular density, and a bleeding diathesis.J Cell Biol. 1998; 140: 419-30Crossref PubMed Scopus (405) Google Scholar, 17Streit M. Riccardi L. Velasco P. Brown L.F. Hawighorst T. Bornstein P. Detmar M. Thrombospondin-2: a potent endogenous inhibitor of tumor growth and angiogenesis.Proc Natl Acad Sci USA. 1999; 96: 14888-93Crossref PubMed Scopus (253) Google Scholar, 18Streit M. Velasco P. Brown L.F. Skobe M. Richard L. Riccardi L. Lawler J. Detmar M. Overexpression of thrombospondin-1 decreases angiogenesis and inhibits the growth of human cutaneous squamous cell carcinomas.Am J Pathol. 1999; 155: 441-52Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar, 19Rodriguez-Manzaneque J.C. Lane T.F. Ortega M.A. Hynes R.O. Lawler J. Iruela-Arispe M.L. Thrombospondin-1 suppresses spontaneous tumor growth and angiogenesis and inhibits activation of matrix metalloprotease-9 and mobilisation of VEGF.Proc Natl Acad Sci USA. 2001; 98: 12485-90Crossref PubMed Scopus (386) Google Scholar, 20Agah A. Kyriakides T.R. Lawler J. Bornstein P. The lack of thrombospondin-1 (TSP1) dictates the course of wound healing in double-TSP1/TSP2-null mice.Am J Pathol. 2002; 161: 831-9Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 21Lawler J. Detmar M. Tumor progression: the effects of thrombospondin-1 and -2.Int J Biochem Cell Biol. 2004; 36: 1038-45Crossref PubMed Scopus (184) Google Scholar, 22Armstrong L.C. Bornstein P. Thrombospondins 1 and 2 function as inhibitors of angiogenesis.Matrix Biol. 2003; 22: 63-71Crossref PubMed Scopus (249) Google Scholar]. Both have been shown to act as negative regulators of angiogenesis and tumor growth in vivo and of endothelial functions in vitro. Knockout and transgenic mice have confirmed their role as endogenous inhibitors in vivo. Fragments of TSP-1 containing type 1 TSP repeats induce apoptosis of endothelial cells in vitro, acting through the cell surface receptor CD36 [43Jimenez B. Volpert O.V. Crawford S.E. Febbraio M. Silverstein R.L. Bouck N. Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1.Nat Med. 2000; 6: 41-8Crossref PubMed Scopus (850) Google Scholar], although proof that the in vivo functions depend on CD36 remains lacking. TSP-1 also inhibits MMP-9 and its release of VEGF from basement membrane; this could provide a second mechanism for inhibition of angiogenesis by TSP-1 [19Rodriguez-Manzaneque J.C. Lane T.F. Ortega M.A. Hynes R.O. Lawler J. Iruela-Arispe M.L. Thrombospondin-1 suppresses spontaneous tumor growth and angiogenesis and inhibits activation of matrix metalloprotease-9 and mobilisation of VEGF.Proc Natl Acad Sci USA. 2001; 98: 12485-90Crossref PubMed Scopus (386) Google Scholar], although, once again, the formal genetic proof that TSP-1 inhibition depends on MMP-9 is lacking. As MMP-9 has both proangiogenic (release of VEGF) and antiangiogenic (release of tumstatin and maybe other ECM fragments, see below) effects, that proof may be difficult to obtain. Basement membrane collagens have also been described as sources of angiogenesis inhibitors, the first being collagen XVIII; a proteolytic fragment of the C-terminal domain of this collagen, endostatin, has been studied for a number of years as an inhibitor of angiogenesis [39Folkman J. Antiangiogenesis in cancer therapy – endostatin and its mechanisms of action.Exp Cell Res. 2006; 312: 594-607Crossref PubMed Scopus (592) Google Scholar]. Endostatin has been reported to bind to integrins (α5β1 and αvβ3) but it is far from clear whether or not those receptors mediate its inhibitory effects on angiogenesis. For example, no dependence on these receptors for function has been demonstrated and some experiments actually show that αvβ3 is not required for its effects either in vitro or in vivo [44Maeshima Y. Sudhakar A. Lively J.C. Ueki K. Kharbanda S. Kahn C.R. Sonenberg N. Hynes R.O. Kalluri R. Tumstatin, an endothelial cell-specific inhibitor of protein synthesis.Scie" @default.
• W2016576487 created "2016-06-24" @default.
• W2016576487 creator A5030647867 @default.
• W2016576487 date "2007-07-01" @default.
• W2016576487 modified "2023-10-14" @default.
• W2016576487 title "Cell–matrix adhesion in vascular development" @default.
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• W2016576487 doi "https://doi.org/10.1111/j.1538-7836.2007.02569.x" @default.
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