© 2000 American Heart Association, Inc.
Editorials |
Bone Sialoprotein and the Paradox of Angiogenesis Versus Atherosclerosis
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 • 
vß3 • angiogenesis • atherosclerosis
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Introduction |
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 Top Introduction References |
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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,
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
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,
vß5, does not bind
BSP, suggesting that there is a certain degree of specificity for the
interaction between BSP and
vß3.
The in vivo data indicating that BSP promotes angiogenesis via
its interaction with
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 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 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-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
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
vß3,
vß5, and
vß1 integrins and
mediates SMC migration specifically via
vß3.9 In
vivo experiments have demonstrated that osteopontin and
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
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
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-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-vß3 interaction is
disrupted by RGD and
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-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.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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