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Circulation Research. 2000;86:827-828

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(Circulation Research. 2000;86:827.)
© 2000 American Heart Association, Inc.

Editorials

Bone Sialoprotein and the Paradox of Angiogenesis Versus Atherosclerosis

Chunming Dong, Pascal J. Goldschmidt-Clermont

From the Heart and Lung Institute and Division of Cardiology, Department of Internal Medicine, College of Medicine and Public Health, Ohio State University, Columbus, Ohio.

Correspondence to Pascal J. Goldschmidt-Clermont, 514 Medical Research Facility, 420 W 12th Ave, Columbus, OH 43210. E-mail Goldschmidt-1{at}medctr.osu.edu


Key Words: bone sialoprotein • {alpha}vß3 • angiogenesis • atherosclerosis


*    Introduction
up arrowTop
 *Introduction
down arrowReferences
 
Bone sialoprotein (BSP) is a protein thought to be highly specific for bone. BSP contains an arginine-glycine-aspartic acid (RGD) cell attachment sequence involved in osteoclast adhesion to bone matrix via the vitronectin receptor and plays an important role in the early process of bone mineralization and resorption. The study by Bellahcène et al1 in this issue of Circulation Research indicates that BSP mediates adhesion and chemotactic migration of endothelial cells and promotes angiogenesis, suggesting that BSP may be an important factor in angiogenesis and the initiation of atherosclerosis, two processes that are probably related.

In earlier studies, Folkman2 hypothesized that tumor growth beyond a few millimeters requires recruitment and growth of a new microcirculation, or angiogenesis, which is induced by tumors as lifelines for oxygen and nutrients. New blood vessels also provide exits for cancer cells to spread to other parts of the body. Angiogenesis is also involved in physiological conditions, such as embryogenesis, and other pathological conditions, such as wound healing. The process of angiogenesis requires a highly coordinated series of events, including endothelial cell proliferation, migration, tube and lumen formation, and, in some cases, recruitment of smooth muscle cells (SMCs) and other adventitial cells.

Adhesive interaction of cells with components of the extracellular matrix is a recognized requirement for cell proliferation and migration. Evidence indicates that many of the adhesive interactions are mediated by members of the integrin family of heterodimeric adhesion receptors. Among these integrins, {alpha}vß3, which is expressed by a variety of cell types, has been shown to play a key role in the cell migration involved in metastasis and angiogenesis.3 The work presented by Bellahcène et al1 indicates that BSP, a bone-associated protein that contains the RGD sequence, a common recognition sequence for most integrins, binds {alpha}vß3 in endothelial cells and mediates the migration of such cells, extending the study by Byzova et al.4 Furthermore, Bellahcène et al1 show that another integrin, {alpha}vß5, does not bind BSP, suggesting that there is a certain degree of specificity for the interaction between BSP and {alpha}vß3.

The in vivo data indicating that BSP promotes angiogenesis via its interaction with {alpha}vß3 integrin and that such an angiogenic effect is probably even greater than that of basic fibroblast growth factor (bFGF)1 are intriguing. These data underscore the physiological and pathophysiological consequences of the interaction between BSP and {alpha}vß3 integrin and define BSP as a novel angiogenic factor. These findings may provide an explanation for the previously established association of BSP expression levels in tumors with the development of bone metastases.5 Higher BSP expression in the tumor correlates with an increased risk of metastasis of carcinomas to bone tissue, which could be due to angiogenesis enhancement by BSP. In addition, BSP expression in the tumor may facilitate tumor cell migration and calcification.

Several families of factors have been implicated in angiogenesis. These include angiogenic factors, such as vascular endothelial growth factor (VEGF) or bFGF, and antiangiogenic factors, such as angiostatin or endostatin.6 Translational research has now been initiated by several centers to test the hypothesis that local delivery of angiogenic agents, especially VEGF and bFGF, by various strategies, including viral vectors, naked DNA, or purified recombinant proteins, may improve blood flow to ischemic tissues in patients with advanced atherosclerosis.7 Similarly, clinical trials for local delivery of antiangiogenic factors, such as angiostatin, using various techniques, are underway to treat patients with malignant tumors.8 Although blockade of BSP interaction with {alpha}vß3 may limit tumor growth and metastasis, the effect of local delivery of BSP to improve blood flow to ischemic tissues, in particular the myocardium, may be complicated by the fact that BSP-{alpha}vß3 interaction may also initiate and aggravate atherosclerosis.

Neointima formation, associated with both atherosclerosis and restenosis, is a complex process that involves SMC migration and proliferation. The molecular mechanisms governing intimal thickening have been a focus of intense research. Numerous studies have indicated a critical role for integrin heterodimers, including {alpha}vß3, in mediating cell-matrix interactions and SMC adhesion and migration, implicating the potential involvement of physiological ligands containing RGD sequence, including BSP, for the activity of such integrins.3 Indeed, in vitro studies have shown that osteopontin, a bone-associated protein closely related to BSP, which contains the RGD sequence, supports SMC adhesion to {alpha}vß3, {alpha}vß5, and {alpha}vß1 integrins and mediates SMC migration specifically via {alpha}vß3.9 In vivo experiments have demonstrated that osteopontin and {alpha}vß3 are expressed in vascular SMCs. In addition, osteopontin expression is upregulated in human atherosclerotic and restenotic lesions.10 Using animal models of neointima formation, several groups have observed increased expression of osteopontin and {alpha}vß3 in such lesions.11 More direct evidence supporting the potential role of osteopontin in the process of intimal thickening stems from the observation that neutralizing antibodies to osteopontin limit neointimal thickening in rat carotid artery after balloon injury.12 RGD and {alpha}vß3 antagonists have been shown to inhibit neointima formation in rabbit, hamster, porcine, and guinea pig vascular injury models, an effect that has been interpreted to be mediated via the disruption of osteopontin-{alpha}vß3 interaction.13 14 The data presented by Bellahcène et al,1 showing that BSP interaction mediates endothelial cell adhesion and migration, implicate the potential role for BSP in atherosclerosis. It is probable that BSP-{alpha}vß3 interaction is disrupted by RGD and {alpha}vß3 antagonists, which may account for, at least in part, the antiatherogenic effect exerted by these agents in the in vivo experiments. Characterization of BSP-{alpha}vß3 interaction and such interaction-induced adhesive and migratory effect on SMCs, examination of BSP expression in vascular lesions, and the use of neutralizing antibodies to BSP in animal models will help clarify the putative role of BSP in the initiation of atherosclerosis and may provide a therapeutic alternative to vascular disease.

Calcification associated with atherosclerotic plaques has been increasingly recognized as an active, regulated process that contributes to the fate of the atherosclerotic plaque, including rupture and subsequent thrombosis.15 However, the molecular determinants regulating extracellular matrix calcification have yet to be identified. Several studies have shown that noncollagenous bone matrix proteins related to BSP, such as osteonectin, osteocalcin, and osteopontin, are found in atherosclerotic vessels and may regulate dystrophic calcification.16 A recent study has shown that BSP is expressed together with osteonectin, osteocalcin, and osteopontin by vascular pericytes.17 Further study is required to examine the expression of BSP and its spatial relationship with early calcification in atherosclerotic plaques to establish the role for BSP in vascular calcification.

The elegant study by Bellahcène et al1 reveals a novel function of BSP as an angiogenic factor. It also opens new research venues to study the role of BSP in the initiation and calcification of atherosclerosis. The relationship between BSP as an angiogenic factor and a factor promoting atherosclerosis or neointimal hyperplasia does not appear to be unique to BSP. It has been shown that microvessels within the advanced atherosclerotic lesions have a high level of VEGF expression. Moreover, intense VEGF expression is noted in totally occlusive lesions with extensive neovascularization.18 The angiogenic factor bFGF may incite, in some instances, aggressive vascular neointimal proliferation.19 Furthermore, anti-angiogenic factors can reduce substantially neointimal formation in animal models of atherosclerosis.20 The dual role of molecules implicated in angiogenesis and atherosclerosis stresses the challenge to scientists seeking a way to promote angiogenesis for ischemic tissues. The success of such efforts will likely require the fine characterization of molecular pathways involved in both angiogenesis and atherosclerosis. Until these pathways are characterized, one might be concerned about progression of atherosclerosis when using angiogenic factors such as BSP, VEGF, or bFGF to treat ischemic heart disease. Although the participation of factors in processes like angiogenesis and atherosclerosis may appear paradoxical, our evolving understanding of advanced atherosclerosis as a misguided form of angiogenesis provides a new target for the design of therapeutic strategies.


*    Footnotes
 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.


*    References
up arrowTop
 up arrowIntroduction
 *References
 

  1. Bellahcène A, Bonjean K, Fohr B, Fedarko NS, Robey FA, Young MF, Fisher LW, Castronovo V. Bone sialoprotein mediates human endothelial cell attachment and migration and promotes angiogenesis. Circ Res. 2000;86:885–891.[Abstract/Free Full Text]
  2. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–1186.
  3. Horton MA. The {alpha}vß3 integrin "vitronectin receptor." Int J Biochem Cell Biol. 1997;29:721–725.[Medline] [Order article via Infotrieve]
  4. Byzova TV, Kim W, Midura RJ, Plow EF. Activation of integrin {alpha}vß3 regulates cell adhesion and migration to bone sialoprotein. Exp Cell Res.. 2000;254:299–308.[Medline] [Order article via Infotrieve]
  5. Bellahcène A, Kroll M, Liebens F, Castronovo V. Bone sialoprotein expression in primary human breast cancer is associated with bone metastases development. J Bone Miner Res. 1996;11:665–670.[Medline] [Order article via Infotrieve]
  6. Kerbel RS. Tumor angiogenesis: past, present and the near future. Carcinogenesis.. 2000;21:505–515.[Abstract/Free Full Text]
  7. Isner JM, Pieczek A, Schainfeld R, Blair R, Haley L, Asahara T, Rosenfield K, Razvi S, Walsh K, Symes JF. Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb. Lancet. 1996;348:370–374.[Medline] [Order article via Infotrieve]
  8. Folkman J. Angiogenesis research: from laboratory to clinic. Forum (Genova). 1999;9(suppl 3):59–62.
  9. Liaw L, Skinner MP, Raines EW, Ross R, Cheresh DA, Schwartz SM, Giachelli CM. The adhesive and migratory effects of osteopontin are mediated via distinct cell surface integrins: role of {alpha}vß3 in smooth muscle cell migration to osteopontin in vitro. J Clin Invest. 1995;95:713–724.
  10. Hoshiga M, Alpers CE, Smith LL, Giachelli CM, Schwartz SM. {alpha}vß3 integrin expression in normal and atherosclerotic artery. Circ Res. 1995;77:1129–1135.[Abstract/Free Full Text]
  11. Corjay MH, Diamond SM, Schlingmann KL, Gibbs SK, Stoltenborg JK, Racanelli AL. {alpha}vß3, {alpha}vß5 and osteopontin are coordinately upregulated at early time points in a rabbit model of neointima formation. J Cell Biochem. 1999;75:492–504.[Medline] [Order article via Infotrieve]
  12. Liaw L, Lombardi DM, Almeida MM, Schwartz SM, deBlois D, Giachelli CM. Neutralizing antibodies directed against osteopontin inhibit rat carotid neointimal thickening after endothelial denudation. Arterioscl Thromb Vasc Biol. 1997;17:188–193.[Abstract/Free Full Text]
  13. Matsuno H, Stassen JM, Moons L, Vermylen J, Hoylaerts MF. Neointima formation in injured hamster carotid artery is effectively prevented by the combination G4120 and quinapril. Thromb Haemost. 1996;76:263–269.[Medline] [Order article via Infotrieve]
  14. Srivatsa SS, Fitzpatrick LA, Tsao PW, Reilly TM, Holmes DRJ, Schwartz RS, Mousa SA. Selective {alpha}vß3 integrin blockade potently limits neointimal hyperplasia and lumen stenosis following deep coronary arterial stent injury: evidence for the functional importance of integrin {alpha}vß3 and osteopontin expression during neointima formation. Cardiovasc Res. 1997;36:408–428.[Abstract/Free Full Text]
  15. Doherty TM, Detrano RC. Coronary arterial calcification as an active process: a new perspective on an old problem. Calcif Tissue Int. 1994;54:224–230.[Medline] [Order article via Infotrieve]
  16. Bini A, Mann KG, Kudryk BJ, Schoen FJ. Noncollagenous bone matrix proteins, calcification, and thrombosis in carotid artery atherosclerosis. Arterioscler Thromb Vasc Biol. 1999;19:1852–1861.[Abstract/Free Full Text]
  17. Doherty MJ, Ashton BA, Walsh S, Beresford JN, Grant ME, Canfield AE. Vascular pericytes express osteogenic potential in vitro and in vivo. J Bone Miner Res. 1998;13:828–838.[Medline] [Order article via Infotrieve]
  18. Inoue M, Itoh H, Ueda M, Naruko T, Kojima A, Komatsu R, Doi K, Ogawa Y, Tamura N, Takaya K, Igaki T, Yamashita J, Chun TH, Masatsugu K, Becker AE, Nakao K. Vascular endothelial growth factor (VEGF) expression in human coronary atherosclerotic lesions: possible pathophysiological significance of VEGF in progression of atherosclerosis. Circulation. 1998;98:2108–2116.[Abstract/Free Full Text]
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