(Circulation. 1997;96:4083-4094.)
© 1997 American Heart Association, Inc.
Articles |
Modulation of Growth Factor Action
Implications for the Treatment of Cardiovascular Diseases
From the Department of Internal Medicine II (Cardiology), Ulm University Medical Center, Ulm, Germany.
Correspondence to Johannes Waltenberger, MD, Department of Internal Medicine II (Cardiology), Ulm University Medical Center, Robert-Koch-Str 8, D-89081 Ulm, Germany. E-mail johannes.waltenberger{at}medizin.uni-ulm.de
 |
Abstract |
|---|
 Top Abstract IntroductionMechanisms of Growth Factor...Growth Factors, Atherosclerosis,...Growth Factors, Myocardial...Growth Factor AntagonismGrowth Factor AgonismGrowth Factor Therapy:...References |
|---|
Abstract Peptide growth factors are involved in fundamental cellular processes relevant for cardiovascular physiology and pathology, namely, atherogenesis and angiogenesis. The modulation of growth factor–related signals represents a novel strategy for the treatment of cardiac and vascular disease. Experimental modulation of growth factor action has already provided a better understanding of cardiovascular biology and pathophysiology. In turn, the development of specific and powerful molecular tools is setting the stage for the exploration of their clinical potentials. Current strategies include the use of recombinant proteins, specific inhibitors of protein-protein interactions, tyrosine kinase inhibitors, the generation and application of dominant-negative molecules, the development of antisense strategies, and a variety of different gene transfer approaches. Parallel avenues of research are heading toward the same goal, the specific suppression of potent pathogenic stimuli that induce and promote atherogenesis or the augmentation of beneficial ones such as induction of therapeutic angiogenesis. The successful application of one of these strategies seems to be in reach and will certainly be a milestone in molecular medicine.
Key Words: growth substances • atherosclerosis • collateral circulation
|
Introduction |
|---|
|
TopAbstractIntroductionMechanisms of Growth Factor...Growth Factors, Atherosclerosis,...Growth Factors, Myocardial...Growth Factor AntagonismGrowth Factor AgonismGrowth Factor Therapy:...References |
|---|
One decade ago, the first clinical trials were conducted to test the potential clinical benefits of recombinant growth factors. Such studies were initially carried out using hematopoetic growth factors such as granulocyte colony–stimulating factor.1 These studies have proven the usefulness of growth factor application for certain hematological disorders. The functional role of some growth factors in various types of cancer has been recognized,2 and strategies to interrupt either growth factor–dependent autocrine tumor growth3,4 or growth factor–dependent tumor angiogenesis5 are being explored. The involvement of growth factors in the pathogenesis of cardiovascular diseases is increasingly recognized,6 including the propagation of diseases such as atherogenesis and restenosis. In addition, growth factors are involved in the stimulation of functional repair processes, including the formation of a functional collateral circulation in the chronic ischemic myocardium.7,8
As are highlighted in this review, the four different growth factors
(PDGF, bFGF, VEGF, and TGF-ß) and their different isoforms,
receptors, and signal transduction machineries play important roles in
the cardiovascular system, namely in atherogenesis and
angiogenesis. All are involved in the functional regulation of one or
more important structures of the vessel wall, namely VSMCs,
endothelial cells or the extracellular matrix (Table 1
). The purpose of this review is to
discuss current options and potential strategies for molecular
interventions related to growth factor action, setting the stage for
the development of novel therapeutic strategies.
|
|
Mechanisms of Growth Factor Action |
|---|
|
TopAbstractIntroductionMechanisms of Growth Factor...Growth Factors, Atherosclerosis,...Growth Factors, Myocardial...Growth Factor AntagonismGrowth Factor AgonismGrowth Factor Therapy:...References |
|---|
Growth factors are potent regulators of cellular function, including proliferation, migration, differentiation, and survival/apoptosis. Growth factor stimulation of cells is a complex and multistep action that transmits extracellular stimuli into the target cell by using various signaling cascades. To better understand the mechanisms and components that form the basis of any molecular strategy of interference, the principals of these cascades are introduced in brief (Fig 1
). Binding
of growth factors to their specific, membrane-bound cell surface
receptors is a key event in the activation process. Binding of growth
factors as PDGF, VEGF, or bFGF to receptors of the transmembrane
tyrosine kinase type initiates a dimerization process, which results in
the activation of the tyrosine kinase domains of the
receptors.9 As a consequence, specific signal
transduction cascades become activated. They can reach the
nucleus, where proliferation and differentiation are modulated, or they
can directly affect the function of cellular proteins such as enzymes
(eg, PI3K) or cytoskeletal proteins. The modulation of gene
transcription can even give rise to indirect effects of growth factors
because the expression of growth factors and their receptors can be
regulated by other growth factors (Table 2).
|
[PLC-
|
The majority of growth factors, such as PDGF, bFGF, or VEGF, stimulate proliferation and migration and inhibit apoptosis. They are positive regulators of the cell cycle. The direct association between growth factor signal and cell cycle regulation, however, is only partially understood. Growth factor stimulation finally results in the production and activation (ie, phosphorylation) of early nuclear proteins that in turn induce transcription of the genes for cyclins, CDKs, and other cell cycle regulators.10 Within the cell cycle, there are two brake-points (G1/S, G2/M) through which the cell must pass before it can enter cell division. Progress through the cell cycle requires the presence of active CDKs, which are activated by cyclins themselves. In response to growth factor stimulation, active CDKs inactivate (ie, phosphorylate) retinoblastoma protein (pRB), a central regulator of the cell cycle. In the quiescent cell, active pRB inhibits cell division by directly inactivating the specific growth-promoting protein E2F, a potent transcription factor. Likewise, overexpression of active pRB inhibits growth factor–stimulated cell division.11 As the central stimulators of the cell cycle, CDKs are functionally regulated themselves by CDK inhibitors such as p21 and p27Kip1. Although overexpression of p21 inhibits cell cycle progression,12 lack of p21 finally results in programmed cell death/apoptosis.13 Similarly, disruption of p27Kip1 in mice gives rise to increased cell proliferation, multiple-organ hyperplasia, and increased body size.14
Unlike PDGF, bFGF, and VEGF, members of the TGF-ß family are negative regulators of the cell cycle that lead to growth arrest by directly affecting the cell cycle (eg, activation of CDK inhibitors), but they have a number of other functions as well. There are three different gene products (TGF-ß1, TGF-ß2, TGF-ß3), which usually form homodimers but can also form heterodimers. TGF-ß binding induces the formation of hetero-oligomeric complexes of different type I and type II serine/threonine kinase receptors,15 which can signal via Smad proteins, a new class of transcription factors.16 Most of the effects of TGF-ß in the cardiovascular system known to date have been gathered for TGF-ß1.
The model of interaction of growth factors with their receptors is
complicated by the fact that there may be different isoforms or splice
variants that can bind to the same or different receptors. This is of
functional importance if a therapeutic strategy is aimed at the
blockade of a specific growth factor/growth factor receptor
interaction. In the case of PDGF, for example, two different genes
encode for two different protein subunits (PDGF A-chain, PDGF B-chain),
which can form either homodimers (PDGF-AA, PDGF-BB) or heterodimers
(PDGF-AB).17 In addition, there are two different
receptor genes giving rise to two different receptor subunits (PDGF
-receptor, PDGF ß-receptor). As a consequence of different
affinities between various ligand and receptor subunits, PDGF-BB can
bind to all PDGF receptor subunits, whereas PDGF-AA can bind only to
PDGF -receptor homodimers, and PDGF-AB cannot bind to PDGF
ß-receptor homodimers.
|
Growth Factors, Atherosclerosis, and Restenosis After Angioplasty |
|---|
|
TopAbstractIntroductionMechanisms of Growth Factor...Growth Factors, Atherosclerosis,...Growth Factors, Myocardial...Growth Factor AntagonismGrowth Factor AgonismGrowth Factor Therapy:...References |
|---|
There is a large body of data available that link growth factor activity to human atherosclerosis and restenosis after angioplasty (reviewed by Ross6). PDGF,17,18 a strong mitogen for mesenchymal cells such as VSMCs and fibroblasts, is regarded as an important mediator of proliferative activity in atherogenesis and restenosis.6 The PDGF-BB isoform is the most potent chemotactic agent known for VSMCs.19 Significant amounts of PDGF are present in the
-granules of platelets, but a number of other
cell types, such as VSMCs,20 leukocytes, and
endothelial cells, do produce and secrete
PDGF.18 Increased levels of PDGF mRNA, PDGF
protein, and PDGF ß-receptor protein can be detected in the
atherosclerotic plaque. On the other hand, the
endothelium of large vessels does not express PDGF
ß-receptors, and PDGF -receptors could be detected only in injured
endothelium.21 In the animal
model, the application of PDGF protein22 or
enhancement of PDGF expression in the vessel
wall23 was sufficient to cause
neointima formation. On the other hand, inhibition of PDGF
activity or inhibition of PDGF ß-receptor production in vivo
resulted in the suppression of arterial remodeling and
intimal thickening24,25 (Table 3). It has been claimed that the
low-molecular-weight compound trapidil (triazolopyrimidine) prevents
restenosis after percutaneous transluminal
coronary angioplasty.26 Trapidil was
initially described as a PDGF
antagonist,27 but the molecular basis
of its action remains to be established. Similar results have been
obtained for bFGF, which is lacking a signal sequence and is found in
the basement membranes and could be released as a result of cell
injury. bFGF was found to stimulate neointima
formation28 (Table 3) and to prevent
apoptosis in VSMCs.29 In turn, inhibition
of bFGF in these cells induces apoptosis, or programmed cell
death.29 Besides proliferation, apoptosis
is being regarded as an important mechanism that regulates intimal
thickening by modulating the cellularity of the
lesion.30
|
Like PDGF, molecules of the TGF-ß family31 are
involved in promoting the pathogenesis of
atherosclerosis.6 TGF-ß exerts
three different actions relevant for cardiovascular
pathology. It stimulates the formation and deposition of extracellular
matrix.32 TGF-ß modifies the response of the
immune system and suppresses inflammatory
processes,33,34 which is thought to have strong
implications for the atherogenic process, as suggested by the finding
of elevated C-reactive protein in unstable
angina.35 In addition, TGF-ß can suppress the
proliferation of VSMCs. It was suggested that VSMC proliferation
inversely relates to the serum levels of lipoprotein(a), which inhibits
plasmin formation and therefore the activation of
TGF-ß.36 Also, TGF-ß has been implicated in
playing the potential role of repairing ischemic injury because
it acts in a cardioprotective manner by reducing the amount of
superoxide anions.31 Targeted expression of
TGF-ß1 promotes vascular endothelial cell DNA
synthesis,37 and TGF-ß1 gene transfer to the
arterial wall stimulates neointima formation in
vivo,38 as does the prolonged administration of
TGF-ß1 protein39 (Table 3
). Taken together, the
inhibitory effects of TGF-ß1,40
PDGF, and possibly bFGF represent promising approaches to
slowing down the atherogenic process or preventing
restenosis.
|
Growth Factors, Myocardial Ischemia, and Angiogenesis |
|---|
|
TopAbstractIntroductionMechanisms of Growth Factor...Growth Factors, Atherosclerosis,...Growth Factors, Myocardial...Growth Factor AntagonismGrowth Factor AgonismGrowth Factor Therapy:...References |
|---|
Atherosclerosis in the heart leads to progressive narrowing or occlusion of coronary arteries, finally resulting in regional myocardial ischemia. Nature has created mechanisms to partially adapt to regional ischemia through "compensatory angiogenesis" (ie, development of a functional collateral circulation), which is driven by angiogenic factors, most of which represent members of the peptide growth factor family.8 However, this adaptive process is rather slow and unable to compensate fully for the effects of ischemia induced by acute occlusion of a coronary artery. It therefore seems to be logical to substitute the angiogenic factor where it is actually needed and where other means of revascularization, such as angioplasty or coronary artery bypass grafting, are not applicable. This novel concept of the therapeutic induction of neovascularization, also denoted "therapeutic angiogenesis" or "molecular bypass grafting," has been demonstrated in a number of different animal models to rapidly induce collateralization in the ischemic area (ie, revascularization) and thereby improve organ function (Table 4
).
|
One angiogenesis-inducing factor is VEGF (reviewed by Thomas41), also identified as vascular permeability factor and vasculotropin. VEGF is an endothelial-specific growth factor that has been shown to be involved in both adaptive and tumor angiogenesis. VEGF exists as five isoforms produced by alternative splicing of mRNA encoded by the same gene.41A Recently, two distinct genes denominated VEGF-B42 and VEGF-C43 have been described; however, their roles in angiogenesis and endothelial regulation remain to be determined. VEGF (or VEGF-A) is upregulated under hypoxic and ischemic conditions in vitro44 and in vivo,45 on both the transcriptional and post-transcriptional level.46 Interestingly, not only the ligand VEGF but also its major signaling receptor KDR/Flk147 is upregulated under hypoxia, which has been shown on the transcriptional level in vivo48 as well as on the protein and the functional level in vitro.49 The exact function of Flt-1 is currently unknown, but it does induce tissue factor expression in endothelial cells as well as in monocytes, and it is involved in monocyte chemotaxis.50 The application of VEGF protein to ischemic limbs51 or ischemic myocardium52–54 in different animal models has proven to be sufficient for the induction of neovascularization, resulting in enhanced tissue perfusion and improved function (recently reviewed by Engler55). Besides its activity in promoting neovascularization, VEGF has been shown to stimulate regrowth of the endothelium after angioplasty,56,57 which is believed to protect the vessel wall against remodeling. Besides KDR and Flt-1, two other receptor tyrosine kinases, Tie-1 and Tie-2, show an endothelial cell–specific expression pattern. Although they play a crucial role in the development of the cardiovascular system (embryonic angiogenesis),58,58a their role in compensatory angiogenesis is currently unknown, and so is the role of the recently identified Tie-2 ligand angiopoietin-1.59
bFGF acts directly on both smooth muscle cells and
endothelial cells; its action in the vessel wall is
therefore not cell type specific.60 bFGF is a
potent stimulator of angiogenesis61 and had been
applied to induce therapeutic angiogenesis in various animal
models62–71 (Table 4). Although some studies
convincingly showed the true formation of new capillaries (ie,
capillary number per fiber number), others62 did
not. Differences in the study protocols (dosage; mode, and time point
of growth factor application) might explain these differences. In
addition to the angiogenic effect, a direct cardioprotective effect of
bFGF has been suggested. With a canine coronary
occlusion/reperfusion model, intracoronary application of bFGF
resulted in a reduction of infarct size after 7 days, whereas
angiogenesis was not (yet) detectable.72
Recently, another member of the FGF-family, namely FGF-5, has been used
to stimulate therapeutic angiogenesis through adenovirus-mediated gene
transfer in a porcine model of myocardial
ischemia.73 Although indirect
parameters such as left ventricular function
(as determined by echocardiography) indicate a
positive effect of the FGF-5 treatment, classic parameters
of induced angiogenesis, such as capillary number per fiber
cross-sectional area or capillary number per fiber number, remained
unchanged. In vitro, the combination of VEGF and bFGF
represents the most potent angiogenic stimulus currently
known.74 In addition, bFGF was found to
upregulate the expression of VEGF75 (Table 2).
However, bFGF has been shown to promote atherogenesis and intimal
hyperplasia,28,60,76 which is potentially
limiting in its use for the stimulation of therapeutic angiogenesis
compared with VEGF. Currently, this issue is
unresolved.77 The same is true for PDGF,
especially for the PDGF-BB isoform,22,23 which
has been shown to be a stimulator of collateral
formation78 and formation of functional vascular
anastomoses.79 Microvascular
endothelial cells express PDGF
ß-receptors80 mediating the angiogenic stimulus
of PDGF.81 Moreover, PDGF-BB is able to
upregulate bFGF,82 FGF
receptor-1,83 and
VEGF.82,84 Therefore, PDGF may act as an indirect
inducer of angiogenesis as well.
The formation of functional collaterals in the
myocardium or ischemic limb, however, is not the
only aspect in which angiogenesis takes place in the
cardiovascular system. The formation of vasa vasorum
within the vessel wall is increasingly recognized as a functional and
morphological aspect of advanced atherosclerosis that
may trigger complications such as rupture of the plaque, consecutive
thrombosis, and tissue infarction.85 The
mediators of this process are currently unknown, but VEGF is
potentially involved in this process while being produced by
arterial smooth muscle cells.86
Likewise, FGF-1, another member of the FGF family, contributes to the
formation of vasa vasorum because overexpression in the vessel wall
leads to capillary formation.87 In this model,
stimulation of plaque angiogenesis was associated with enhanced
neointima formation, raising the possibility that enhanced
perfusion of the plaque results in an accelerated atherogenic process.
The task of functional interference with plaque angiogenesis has not
been addressed yet. It is an interesting perspective, that the
inhibition of plaque angiogenesis represents a potential means
of reducing the progression of atherosclerosis and
limiting its complications (Fig 2). On
the other hand, promotion of plaque angiogenesis and
neointima formation might be unwanted side effects of
therapeutic angiogenesis.
|
|
Growth Factor Antagonism |
|---|
|
TopAbstractIntroductionMechanisms of Growth Factor...Growth Factors, Atherosclerosis,...Growth Factors, Myocardial...Growth Factor AntagonismGrowth Factor AgonismGrowth Factor Therapy:...References |
|---|
A large variety of different approaches has been developed to antagonize the action of growth factors, as listed in Table 5
and illustrated in Fig 1. Examples are
given preferentially for PDGF and VEGF.
|
Functional inhibition of growth factor binding to its receptor or
receptors is a potent strategy that can be realized by a variety of
different compounds, some of which are purely experimental and some of
which could be further developed and explored with regard to their
clinical potentials. Neutralizing antibodies recognizing either PDGF or
VEGF have been used to antagonize the function of these growth factors
in vitro and in vivo. PDGF antagonism results in the inhibition of
neointimal smooth muscle cell accumulation secondary to
angioplasty and consecutive suppression of arterial
remodeling in the rat,24 and inhibition of VEGF
leads to reduced vascular permeability.88 Binding
inhibitors such as polyanionic substances like
neomycin89 or synthetic peptides derived from a
growth factor sequence that specifically block the interaction of PDGF
with its receptors90 can revert the action
of PDGF in vitro. Neomycin was even found to discriminate between
the two subtypes of PDGF receptors because it prevents binding
of PDGF-BB to the PDGF ß-receptor but not to the PDGF
-receptor.89 Heparin-mimicking compounds have
been shown to inhibit the interaction of heparin-binding growth factors
to the extracellular matrix (also referred to as "low-affinity
receptors"), exerting an antiproliferative activity to
VSMCs.91 Suramin, a
polysulfonyl-naphthyl-urea compound originally developed as an
anti-trypanosomal agent, is a potent compound interfering with the
binding of a variety of growth factors to their high-affinity receptors
and consecutively inhibiting growth factor action. This has been shown
for PDGF,92 bFGF,93 and
VEGF in vitro94 as well as in
vivo.95 In an endothelial
denudation model in the rabbit, suramin was shown to inhibit intimal
thickening.96 In a similar way,
2-bromomethyl-5-chlorobenzene sulfonylphthalimide antagonizes PDGF
action in vitro in a rather specific fashion, inhibiting intimal lesion
formation in vivo.97 Finally, a novel group of
functional binding inhibitors are represented
by high-affinity RNA or DNA ligands, which have the potency of
functionally antagonizing VEGF98 and the PDGF
B-chain.99
Growth factor receptor blockers of the tyrphostin
class100 or the 2-phenylaminopyrimidine
class101 of PTK inhibitors have
turned out to be promising candidates for a clinically useful strategy.
These low-molecular-weight compounds inhibit the enzymatic activity of
tyrosine kinases, which, as shown for PDGF, work in the in vitro
situation.3,102 Some, but not all, however, work
in the in vivo situation as well.103 Recently, it
has been possible to identify compounds (eg, AG1296) with high
selectivity even between closely related protein tyrosine kinases such
as the PDGF receptors and the VEGF receptor KDR.3
This finding provides the basis for specific, differential approaches
such as inhibition of restenosis, which is based on the
postulate that PDGF-dependent proliferation and migration of smooth
muscle cells are inhibited, whereas VEGF-dependent regeneration of the
endothelium should be unaltered in large vessels (Table 1).
Mutations or truncations within the growth factor or growth factor receptor molecules can abolish their function. The PDGF ß-receptor,104 the VEGF receptor Flk-1/KDR,5 but also the TGF-ß type II receptor105 made devoid of a functional kinase domain (ie, dominant-negative growth factor receptor mutants) make cells unresponsive for the corresponding ligand. When overexpressed in the target cell, growth factor binding results in the formation of nonfunctional heterodimers with the wild-type receptor, unable to induce receptor autophosphorylation and activation. A dominant-negative Flk-1 mutant has been shown to inhibit glioblastoma growth through inhibition of angiogenesis in vivo.5 A conceptually different approach is the use of soluble growth factor receptors, which bind the ligand in the liquid phase and therefore competitively prevent ligand binding to functional cell surface receptors, as shown for PDGF.106 Recently, several endogenous soluble Flt-1 molecules have been identified.107,108 Because of their high affinity to VEGF, they are ideal candidates for VEGF inhibition. Their function and in vivo regulation are not known yet; however, in vitro studies using soluble Flt-1 receptors demonstrate their potency as functional antagonists of VEGF-induced proliferation107 and migration of endothelial cells (unpublished results). The concept of dominant-negative mutant molecules has also been explored on the ligand side. PDGF-0, a mutant PDGF molecule that is unable to dimerize and induce dimerization of PDGF receptors, competitively inhibits endogenous PDGF.4 Recently, the first naturally occurring antagonist for a growth factor receptor was identified in Drosophila.109 The identification of human homologs will open the way for novel approaches in molecular medicine.
Further downstream within the target cell, other modes of the
inhibition of growth factor signal transduction represent a
promising strategy, previously described as "signal transduction
therapy." The idea is to interrupt the growth factor–induced signal
at well defined steps within the signal-transduction cascade (Fig 1). A
number of different compounds are currently being developed such as SH2
blockers, SH3 blockers, Ras exchange blockers, Ras farnesylation
inhibitors, Raf1 blockers, and blockers of the
MAPK.100 This may even allow the selective
inhibition of isolated effects such as proliferation while others (eg,
chemotaxis) remain intact. Gene transfer inducing the overexpression of
negative regulators of the cell cycle such as active
pRb11 or p2112 resulted in
a reduction of neointima formation in different animal
models (Table 3). One has to be aware that in contrast to most of the
other approaches discussed, the inhibition of the cell cycle is not a
specific intervention (ie, not specific for a specific growth factor or
a cell type). Such an approach does make sense, however, if the
targeted cell type is well defined and a local delivery approach is
successful, both of which might be realized in the prevention of
restenosis. Through interference with microtubule function (an
even further downstream event), taxol disrupts several growth
factor–stimulated processes in the cell, such as locomotion,
alteration of cell shape, and growth factor–induced proliferation. In
a rat carotid artery injury model, taxol inhibits PDGF-BB–induced VSMC
invasion/chemotaxis through inhibition of the PDGF-BB–induced changes
in locomotion and/or shape changes, resulting in inhibition of
PDGF-induced cell proliferation and neointimal accumulation
of smooth muscle cells in vivo.110
Antisense oligodeoxynucleotides may be used to suppress the
translation of a specific molecule,111,112 such
as a growth factor, its receptor, or downstream molecules involved in
mitogenic signaling. Inhibition of PDGF
A-chain,113 PDGF
B-chain,114 bFGF,29 or the
PDGF ß-receptor114 have been shown in vitro,
and the effects of antisense inhibition of
VEGF115 and of the PDGF
ß-receptor25 have recently been shown in vivo.
Other successful in vivo applications of this technique have been
demonstrated for downstream proliferation-associated molecules such as
c-myb116 (Table 3a), although there is
substantial concern about the specificity of such an
approach117 (see below).
Recombinant chimeric/hybrid molecules use the high binding specificity of the growth factor component and the cell-specific expression pattern of the corresponding growth factor receptors to target chemicals and drugs. Saponin linked to bFGF is able to abolish VSMC proliferation in vitro and neointima formation in vivo.118–120 Likewise, diphtheria toxin–conjugated VEGF is able to inhibit endothelial cell proliferation in vitro and neovascularization in vivo.121 These approaches are specific, potent, and clinically attractive.
A potentially useful approach for growth factor antagonism is represented by the application of angiopeptin, an octapeptide, which has been shown to inhibit neointima formation in a variety of animal models of atherosclerosis.122,123 Furthermore, there are initial, preliminary reports on its usefulness in human beings for suppression of neointima formation in transplant atherosclerosis.124 The exact mechanism of angiopeptin action is currently unknown; however, there is evidence of complex functional antagonism of IGF-1 as well as a number of other growth factors.122
Because of its different mechanism of action by signaling via membrane-bound serine/threonine kinases,15 slightly modified concepts are required for the antagonism of local TGF-ß activity on the receptor and downstream-signaling level (ie, serine/threonine kinase inhibitors). In addition to the concepts discussed, there is the extracellular matrix proteoglycan decorin, a natural inhibitor of TGF-ß, which binds TGF-ß and was shown to function in vivo by protecting against scarring in experimental kidney disease.125
|
Growth Factor Agonism |
|---|
|
TopAbstractIntroductionMechanisms of Growth Factor...Growth Factors, Atherosclerosis,...Growth Factors, Myocardial...Growth Factor AntagonismGrowth Factor AgonismGrowth Factor Therapy:...References |
|---|
Once a specific and potent function of a molecule has been established, it is a rational and straightforward approach to apply this molecule to enhance its biological activity in situations in which the naturally occurring molecule is believed to be inefficiently expressed. This can most easily be achieved through the local28 or regional52 application of the mature protein, which can be made available in large quantities with the use of recombinant DNA technology. In a number of situations, however, systemic application may be feasible.69 This is likely to be the case for the stimulation of therapeutic angiogenesis because relevant receptors are upregulated by hypoxia,48,49 leading to a response localized to the area of interest.126
Other alternatives have been developed on the basis of gene transfer
technology. The transfer of a specific gene, controlled by a suitable
promotor, can give rise to the production of recombinant
proteins at the area of interest.127 As
demonstrated in various animal models, advancements of transfer
technology result in an increasing local restrictability of foreign
gene expression. Depending on a variety of factors, gene therapy could
be accomplished ex vivo (eg, when the vascular wall or intravascular
stents are seeded with genetically modified
cells)128 or in vivo through the use of different
shuttles, such as retroviruses, adenoviruses, or
liposomes.129 It should be emphasized that the
transfection efficiency and time course of transgene expression show
great variability depending on the type of vector used and the
susceptibility of various cell types. As an experimental tool with
which to study vessel wall biology, gene transfer experiments have
already provided valuable data about the functional significance of
individual factors. For example, the transfer of both PDGF-BB and
TGF-ß resulted in the stimulation of neointima formation
in the arterial wall (Table 3b). The induction of
angiogenesis could be shown in different in vivo models using
replication-deficient recombinant adenovirus vectors encoding the
sequence of VEGF130 or
FGF-5.73
Recent data give support to the idea that certain drugs may be able to enhance the expression of certain growth factors. In fact, there is first evidence from a clinical study that aspirin stimulates TGF-ß activation via a so-far-unidentified pathway.131 Because elevated TGF-ß levels can be correlated with a decrease in VSMC proliferation, it is conceivable that the aspirin-induced retardation of the atherosclerotic progression and the consecutive decrease in incidence of myocardial infarction132 may be explained in part (besides inhibition of platelet aggregation) by TGF-ß induction. A similar effect of drug-induced TGF-ß upregulation could be observed for anti-estrogens such as tamoxifen, resulting in the inhibition of VSMC proliferation in vitro133 and the suppression of diet-induced formation of lipid lesions in the mouse aorta in vivo.134
|
Growth Factor Therapy: Strategies and Current Limitations |
|---|
|
TopAbstractIntroductionMechanisms of Growth Factor...Growth Factors, Atherosclerosis,...Growth Factors, Myocardial...Growth Factor AntagonismGrowth Factor AgonismGrowth Factor Therapy:...References |
|---|
Several principles are available for the inhibition or stimulation of growth factor action that have been successfully applied in the animal model to modify neointima formation or induce angiogenesis (Fig 2
and Tables 3 and 4), whereas hematopoietic growth
factors are already used in the treatment of humans. Concerning the
treatment of cardiovascular diseases, the first human
gene therapy trial is under way.135,136 The idea
is to induce therapeutic angiogenesis in peripheral
arterial occlusive disease through local application of
plasmids (naked DNA) encoding VEGF (rhVEGF165).
Although this is an interesting approach, a number of fundamental
questions, such as the level of transgene expression, remain to be
elucidated until it can be generally accepted as a rational treatment
option. An alternative to intravascular DNA application could be the
direct intramuscular gene transfer,137 which
should even be feasible in patients with extensive
peripheral vascular disease. Most recently, the first
clinical phase I trials have been initiated to evaluate the feasibility
of therapeutic angiogenesis in the human heart prone to
coronary artery disease. The researchers will investigate the
intracoronary application of recombinant bFGF (performed at the
National Institutes of Health, quoted in Reference 138138 ), the
application of VEGF (Genentech announcement, January 21, 1997), or the
extravascular application of recombinant bFGF applied locally to the
extravascular surface of a coronary artery that could not be
otherwise revascularized.138
A number of unresolved questions, however, are limiting and, at the
present time, prohibiting the immediate clinical use of growth
factors in the treatment of cardiovascular disorders.
For all the different approaches described, there are unresolved
questions concerning specificity, potency, feasibility, and short- and
long-term side effects in the human situation. There are general
limitations to the use of antisense
technology.112,139 When used under proper
circumstances, this powerful tool may be applied successfully. However,
recent findings point out the potential nonspecificity and lack of
consistency, partly explained by an aptamer
effect.140 On the other hand, there is evidence
that part of the "unspecific" effect of some phosphorothioate
oligodeoxynucleotides is based on their ability to directly
bind the heparin-binding growth factor bFGF, consecutively preventing
growth factor binding to its receptors, and therefore resulting in
another mode of growth factor antagonism, which deserves further
exploration.141 In addition, it was recently
shown that the inhibitory effects of antisense approaches
targeting c-myb and c-myc and resulting in the
inhibition of neointima formation after experimental
angioplasty (Table 3a) are dependent on a stretch of four contiguous
guanosine (G4) residues and therefore do not represent true
antisense approaches.117
Immunological problems (antiglobulin response) are associated with the application of neutralizing antibodies. Therefore, attempts to humanize and modify such antibodies are under way.142 Synthetic peptides, on the other hand, vary widely in their toxic potential; some are tolerated well (such as angiopeptin124), and others are highly toxic even to cells in vitro90. Major obstacles complicating gene transfer approaches are to be clarified, including the uptake of constructs into cells, the reproducibility of recombinant gene expression, and transfer efficiency (ie, sufficient therapeutic protein levels). Moreover, minimization of virus-associated vascular pathology and the question of optimal virus composition and concentration remain issues to be resolved143,144 until a broader application in humans can be carried out reasonably and safely.
When applying or overexpressing growth factors or stimulating growth factor–dependent pathways, one should be aware of potential activation of autocrine loops, which could result in the development of cancer.2 In the case of VEGF, however, no such effect has been observed so far. In fact, VEGF did not promote transformation when overexpressed in Chinese hamster ovary cells, but it conferred a growth advantage in vivo on the basis of its angiogenic properties.145
For many approaches, a safe local delivery of the substance is sought to minimize potential side effects of the molecular intervention. In the case of intravascular applications, for example, local delivery catheters have been developed, such as double-balloon catheters, porous balloons, or devices allowing perfusion of the segment distal to the catheter tip. At the present time, however, none of the systems available allow perfect restrictability of the applied agent together with good distal perfusion of the myocardium.146 In consequence, some of the approaches discussed above cannot be undertaken at the present time—at least not without some risk of local or systemic side effects. Whether this fact will be limiting to current or future developments is presently unknown. An alternative approach aimed at the localized application of drugs to the vessel wall is the use of intravascular stents seeded with endothelial cells, which may be genetically modified and may express and secrete the protein of choice.128 Analogously, drug-coated stents may serve to target diffusible molecules to the intima and media of the vessel wall. The feasibility of this principle has been demonstrated through the use of heparin-coated stents.147
Finally, one should be aware that many growth factors have different functions in the body depending on the localization and cell type upon which they are acting. Therefore, therapeutic approaches should be as specific and restricted as possible. Only future in vivo testing will reveal the functional significance of the various actions in a given situation of molecular intervention. Nevertheless, our current technical and technological possibilities are limited, and further development in this promising field is required, for both the growth factors mentioned and other growth factors of potential importance. However, it seems only a question of time before theoretical considerations and experimental approaches regarding growth factor modulation will find their way into clinical practice.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This work was supported in part by grants from Deutsche Forschungsgemeinschaft, Fritz-Thyssen-Stiftung, Cologne, and Dr Mildred-Scheel-Stiftung, Bonn. I thank all of my colleagues in the field for fruitful discussions. I am especially grateful to Carl-Henrik Heldin (Uppsala) and Frank Böhmer (Jena) for critically reading of the manuscript. I apologize for not having been able to cite all relevant literature because of the magnitude of available data and because the length of the reference list must be limited due to editorial policy.
|
References |
|---|
|
TopAbstractIntroductionMechanisms of Growth Factor...Growth Factors, Atherosclerosis,...Growth Factors, Myocardial...Growth Factor AntagonismGrowth Factor AgonismGrowth Factor Therapy:...References |
|---|
-
Bronchud MH, Scarffe JH, Thatcher N, Crowther D,
Souza LM, Alton NK, Testa NG, Dexter TM. Phase I/II study of
recombinant human granulocyte colony-stimulating factor in patients
receiving intensive chemotherapy for small cell lung cancer.
Br J Cancer.. 1987;56:809–813.[Medline]
[Order article via Infotrieve]
-
Sporn MB, Roberts AB. Autocrine growth factors and
cancer. Nature. 1985;313:745–747.[Medline]
[Order article via Infotrieve]
-
Kovalenko M, Gazit A, Böhmer A, Rorsman C,
Heldin C-H, Waltenberger J, Böhmer F-D, Levitzki A. Selective
platelet-derived growth factor receptor kinase blockers reverse
sis-transformation. Cancer Res.. 1994;54:6106–6114.
[Abstract/Free Full Text]
-
Vassbotn FS, Andersson M, Westermark B, Heldin C-H,
Östman A. Reversion of autocrine transformation by a dominant
negative platelet-derived growth factor mutant. Mol Cell
Biol. 1993;13:4066–4076.
[Abstract/Free Full Text]
-
Millauer B, Shawver LK, Plate KH, Risau W, Ullrich
A. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1
mutant. Nature. 1994;367:576–579.[Medline]
[Order article via Infotrieve]
-
Ross R. The pathogenesis of
atherosclerosis: a perspective for the 1990s.
Nature. 1993;362:801–809.[Medline]
[Order article via Infotrieve]
-
Schaper W, Schaper J, eds. Collateral
Circulation: Heart, Brain, Kidney, Limbs. Boston/Dordrecht/London:
Kluwer Academic Publishers; 1993.
-
Schaper W, Ito WD. Molecular mechanisms of
coronary collateral vessel growth. Circ Res. 1996;79:911–919.
[Free Full Text]
-
Claesson-Welsh L. Mechanism of action of
platelet-derived growth factor. Int J Biochem Cell
Biol. 1996;28:373–385.[Medline]
[Order article via Infotrieve]
-
Nasmyth K. Viewpoint: Putting the cell cycle in
order. Science. 1996;274:1643–1645.
[Free Full Text]
-
Chang MW, Barr E, Seltzer J, Jiang YQ, Nabel GJ,
Nabel EG, Parmacek MS, Leiden JM. Cytostatic gene therapy for vascular
proliferative disorders with a constitutively active form of the
retinoblastoma gene product. Science. 1995;267:518–522.
[Abstract/Free Full Text]
-
Chang MW, Barr E, Lu MM, Barton K, Leiden JM.
Adenovirus-mediated over-expression of the cyclin/cyclin-dependent
kinase inhibitor p21 inhibits vascular smooth muscle cell
proliferation and neointima formation in the rat carotid
artery model of balloon angioplasty. J Clin Invest. 1995;96:2260–2268.
-
Waldman T, Lengauer C, Kinzler KW, Vogelstein B.
Uncoupling of S phase and mitosis induced by anticancer agents in cells
lacking p21. Nature. 1996;381:713–716.[Medline]
[Order article via Infotrieve]
-
Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T,
Shishido N, Horii I, Loh DY, Nakayama K-i. Mice lacking
p27Kip1 display increased body size, multiple
organ hyperplasia, retinal dysplasia, and pituitary tumors.
Cell. 1996;85:707–720.[Medline]
[Order article via Infotrieve]
-
ten Dijke P, Miyazono K, Heldin C-H. Signaling via
hetero-oligomeric complexes of type I and type II serine/threonine
kinase receptors. Curr Opin Cell Biol. 1996;8:139–145.[Medline]
[Order article via Infotrieve]
-
Hill CS. Signalling to the nucleus by members of the
transforming growth factor-ß (TGF-ß) superfamily. Cell
Signal. 1996;8:533–544.[Medline]
[Order article via Infotrieve]
-
Heldin C-H. Structural and functional studies on
platelet-derived growth factor. EMBO J. 1992;11:4251–4259.[Medline]
[Order article via Infotrieve]
-
Raines EW, Bowen-Pope DF, Ross R.
Platelet-derived growth factor. In: Sporn MB, Roberts AB, eds.
Handbook of Experimental Pharmacology: Peptide Growth Factors and
Their Receptors. Heidelberg: Springer-Verlag; 1990:173–262.
-
Bornfeldt KE, Raines EW, Nakano T, Graves LM, Krebs
EG, Ross R. Insulin-like growth factor-1 and platelet-derived
growth factor-BB induce directed migration of human
arterial smooth muscle cells via signaling pathways that
are distinct from those of proliferation. J Clin
Invest. 1994;93:1266–1274.
-
Calara F, Ameli S, Hultgårdh-Nilsson A, Cercek B,
Kupfer J, Hedin U, Forrester J, Shah PK, Nilsson J. Autocrine induction
of DNA synthesis by mechanical injury of cultured smooth muscle cells:
potential role of FGF and PDGF. Arterioscler Thromb Vasc
Biol. 1996;16:187–193.
[Abstract/Free Full Text]
-
Lindner V, Reidy MA. Platelet-derived growth
factor ligand and receptor expression by large vessel
endothelium in vivo. Am J Pathol.. 1995;146:1488–1497.[Abstract]
-
Jawien A, Bowen-Pope DF, Lindner V, Schwartz SM,
Clowes AW. Platelet-derived growth factor promotes smooth muscle
migration and intimal thickening in a rat model of balloon angioplasty.
J Clin Invest. 1992;89:507–511.
-
Nabel EG, Yang Z, Liptay S, San H, Gordon D,
Haudenschild CC, Nabel GJ. Recombinant platelet-derived growth
factor B gene expression in porcine arteries induce intimal hyperplasia
in vivo. J Clin Invest. 1993;91:1822–1829.
-
Ferns GAA, Raines EW, Sprugel KH, Motani AS, Reidy
MA, Ross R. Inhibition of neointimal smooth muscle
accumulation after angioplasty by an antibody to PDGF.
Science. 1991;253:1129–1132.
[Abstract/Free Full Text]
-
Sirois MG, Simons M, Edelman ER. Antisense
oligonucleotide inhibition of PDGFR-ß receptor
subunit expression directs suppression of intimal thickening.
Circulation. 1997;95:669–676.
[Abstract/Free Full Text]
-
Okamoto S, Inden M, Setsuda M, Konishi T, Nakano T.
Effects of trapidil (triazolopyrimidine), a platelet-derived growth
factor antagonist, in preventing restenosis after
percutaneous transluminal coronary angioplasty.
Am Heart J. 1992;123:1439–1444.[Medline]
[Order article via Infotrieve]
-
Ohnishi H, Yamaguchi K, Shimada S, Suzuki Y, Kumagai
A. A new approach to the treatment of atherosclerosis
and trapidil as an antagonist to platelet-derived
growth factor. Life Sci. 1981;28:1641–1646.[Medline]
[Order article via Infotrieve]
-
Edelman ER, Nugent MA, Smith LT, Karnovsky MJ. Basic
fibroblast growth factor enhances the coupling of intimal hyperplasia
and proliferation of vasa vasorum in injured rat arteries. J
Clin Invest. 1992;89:465–473.
-
Fox JC, Shanley JR. Antisense inhibition of basic
fibroblast growth factor induces apoptosis in vascular smooth
muscle cells. J Biol Chem. 1996;271:12578–12584.
[Abstract/Free Full Text]
-
Schwartz SM, Bennett MR. Death by any other name.
Am J Pathol. 1995;147:229–234.[Medline]
[Order article via Infotrieve]
-
Roberts AB, Sporn MB.
Physiological actions and clinical applications of
transforming growth factor-ß (TGF-ß). Growth
Factors. 1993;8:1–9.[Medline]
[Order article via Infotrieve]
-
Waltenberger J, Lundin L, Öberg K, Wilander E,
Miyazono K, Heldin C-H, Funa K. Involvement of transforming growth
factor-ß in the formation of fibrotic lesions in carcinoid heart
disease. Am J Pathol. 1993;142:71–78.[Abstract]
-
Waltenberger J, Wanders A, Fellström B,
Miyazono K, Heldin C-H, Funa K. Induction of transforming growth
factor-ß during cardiac allograft rejection. J
Immunol. 1993;151:1147–1157.[Abstract]
-
Waltenberger J, Akyürek ML, Aurivillius M,
Wanders A, Larsson E, Fellström B, Funa K.
Ischemia-induced transplant
arteriosclerosis in the rat: induction of peptide
growth factor expression. Arterioscler Thromb Vasc Biol. 1996;16:1516–1523.
[Abstract/Free Full Text]
-
Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL,
Rebuzzi AG, Pepys MB, Maseri A. The prognostic value of C-reactive
protein and serum amyloid protein A in severe unstable angina.
N Engl J Med. 1994;331:417–424.
[Abstract/Free Full Text]
-
Grainger DJ, Kirschenlohr HL, Metcalfe JC, Weissberg
PL, Wade DP, Lawn RM. Atherogenic lipoprotein(a) promotes the
proliferation of human smooth muscle cells. Science. 1993;260:1655–1658.
[Abstract/Free Full Text]
-
Koh GY, Kim S-J, Klug MG, Park K, Soonpaa MH, Field
LJ. Targeted expression of transforming growth factor-ß1 in
intracardiac grafts promotes vascular endothelial cell
DNA synthesis. J Clin Invest. 1995;95:114–121.
-
Nabel EG, Shum L, Pompili VJ, Yang Z-Y, San H, Shu
HB, Liptay S, Gold L, Gordon D, Derynck R, Nabel GJ. Direct transfer of
transforming growth factor ß1 gene into arteries stimulates
fibrocellular hyperplasia. Proc Natl Acad Sci U S A.. 1993;90:10759–10763.
[Abstract/Free Full Text]
-
Kanzaki T, Tamura K, Takahashi K, Saito Y, Akikusa B,
Oohashi H, Kasayuki N, Ueda M, Morisaki N. In vivo effect of
TGF-ß1: enhanced intimal thickening by administration of
TGF-ß1 in rabbit arteries injured with a balloon catheter.
Arterioscler Thromb Vasc Biol. 1995;15:1951–1957.
[Abstract/Free Full Text]
-
Wolf YG, Rasmussen LM, Ruoslahti E. Antibodies
against transforming growth factor-ß1 suppress intimal
hyperplasia in a rat model. J Clin Invest. 1994;93:1172–1178.
-
Thomas KA. Vascular endothelial
growth factor, a potent and selective angiogenic agent. J
Biol Chem. 1996;271:603–606.
[Free Full Text]
-
Poltorak Z, Cohen T, Sivan R, Kandelis Y, Spira G, Vlodavsky
I, Keshet E, Neufeld G. VEGF(145), a secreted vascular endothelial
growth factor isoform that binds to extracellular matrix. J Biol
Chem.. 1997;272:7151–7158.
[Abstract/Free Full Text]
-
Olofsson B, Pajusola K, Kaipainen A, von Euler G,
Joukov V, Saksela O, Orpana A, Pettersson RF, Alitalo K, Eriksson U.
Vascular endothelial growth factor B, a novel growth
factor for endothelial cells. Proc Natl Acad Sci
U S A.. 1996;93:2576–2581.
[Abstract/Free Full Text]
-
Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen
I, Kukk E, Saksela O, Kalkkinen N, Alitalo K. A novel vascular
endothelial growth factor, VEGF-C, is a ligand for the
Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO
J. 1996;15:290–298.[Medline]
[Order article via Infotrieve]
-
Shweiki D, Itin A, Soffer D, Keshet E. Vascular
endothelial growth factor induced by hypoxia
may mediate hypoxia-initiated angiogenesis. Nature. 1992;359:843–845.[Medline]
[Order article via Infotrieve]
-
Banai S, Shweiki D, Pinson A, Chandra M, Lazarovici
G, Keshet E. Upregulation of vascular endothelial
growth factor expression induced by myocardial ischaemia: implications
for coronary angiogenesis. Cardiovasc Res. 1994;28:1176–1179.
[Abstract/Free Full Text]
-
Ikeda E, Achen MG, Breier G, Risau W. Hypoxia-induced
transcriptional activation and increased mRNA stability of vascular
endothelial growth factor in C6 glioma cells.
J Biol Chem. 1995;270:19761–19766.
[Abstract/Free Full Text]
-
Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya
M, Heldin C-H. Different signal transduction properties of
KDR and Flt1, two receptors for vascular
endothelial growth factor. J Biol Chem. 1994;269:26988–26995.
[Abstract/Free Full Text]
-
Tuder RM, Flook BE, Voelkel NF. Increased gene
expression for VEGF and the VEGF receptors KDR/Flk and
Flt in lungs exposed to acute or to chronic hypoxia.
J Clin Invest. 1995;95:1798–1807.
-
Waltenberger J, Mayr U, Pentz S, Hombach V.
Functional upregulation of the vascular endothelial
growth factor receptor KDR by hypoxia. Circulation. 1996;94:1647–1654.
[Abstract/Free Full Text]
-
Clauss M, Weich H, Breier G, Knies U, Röckl W,
Waltenberger J, Risau W. The vascular endothelial
growth factor receptor FLT-1 mediates biological activities:
implications for a functional role of placenta growth factor in
monocyte activation and chemotaxis. J Biol Chem. 1996;271:17629–17634.
[Abstract/Free Full Text]
-
Takeshita S, Zheng LP, Brogi E, Kearney M, Pu L-Q,
Bunting S, Ferrara N, Symes JF, Isner JM. Therapeutic angiogenesis: a
single intraarterial bolus of vascular
endothelial growth factor augments
revascularization in a rabbit ischemic hind
limb model. J Clin Invest. 1994;93:662–670.
-
Banai S, Jaklitsch MT, Shou M, Lazarous DF,
Scheinowitz M, Biro S, Epstein SE, Unger EF. Angiogenic-induced
enhancement of collateral blood flow to ischemic
myocardium by vascular endothelial growth
factor in dogs. Circulation. 1994;89:2183–2189.
[Abstract/Free Full Text]
-
Pearlman JD, Hibberd MG, Chuang ML, Harada K, Lopez
JJ, Gladstone SR, Friedman M, Sellke FW, Simons M. Magnetic resonance
mapping demonstrates benefits of VEGF-induced myocardial angiogenesis.
Nat Med. 1995;1:1085–1089.[Medline]
[Order article via Infotrieve]
-
Harada K, Friedman M, Lopez JJ, Wang SY, Li J, Prasad
PV, Pearlman JD, Edelman ER, Sellke FW, Simons M. Vascular
endothelial growth factor administration in chronic
myocardial ischemia. Am J Physiol. 1996;270:H1791–H1802.
[Abstract/Free Full Text]
-
Engler DA. Use of vascular
endothelial growth factor for therapeutic angiogenesis.
Circulation. 1996;94:1496–1498.
[Free Full Text]
-
Callow AD, Choi ET, Trachtenberg JD, Stevens SL,
Connolly DT, Rodi C, Ryan US. Vascular permeability factor accelerates
endothelial regrowth following balloon angioplasty.
Growth Factors. 1994;10:223–228.[Medline]
[Order article via Infotrieve]
-
Asahara T, Bauters C, Pastore C, Kearney M, Rossow S,
Bunting S, Ferrara N, Symes JF, Isner JM. Local delivery of vascular
endothelial growth factor accelerates
reendothelialization and attenuates intimal hyperplasia
in balloon-injured rat carotid artery. Circulation. 1995;91:2793–2801.
[Abstract/Free Full Text]
-
Merenmies J, Parada LF, Henkenmeyer M. Receptor
tyrosine kinase signaling in vascular development. Cell Growth
Differ. 1997;8:3–10.[Medline]
[Order article via Infotrieve]
-
Risau W. Mechanisms of angiogenesis. Nature. 1997;386:671–674.[Medline]
[Order article via Infotrieve]
-
Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre
PC, Davis S, Sato TN, Yancopoulos GD. Requisite role of angiopoietin-1,
a ligand for the TIE2 receptor, during embryonic angiogenesis.
Cell. 1996;87:1171–1180.[Medline]
[Order article via Infotrieve]
-
Lindner V, Reidy MA. Expression of basic fibroblast
growth factor and its receptor by smooth muscle cells and
endothelium in injured rat arteries: an en face study.
Circ Res. 1993;73:589–595.
[Abstract/Free Full Text]
-
Folkman J, Shing Y. Angiogenesis. J Biol
Chem. 1992;267:10931–10934.
[Free Full Text]
-
Yanagisawa-Miwa A, Uchida Y, Nakamura F, Tomaru T,
Kido H, Kamijo T, Sugimoto T, Kaji K, Utsuyama M, Kurashima C, Ito H.
Salvage of infarcted myocardium by angiogenic action of
basic fibroblast growth factor. Science. 1992;257:1401–1403.
[Abstract/Free Full Text]
-
Baffour R, Berman J, Garb JL, Rhee SW, Kaufman J,
Friedmann P. Enhanced angiogenesis and growth of collaterals by in vivo
administration of recombinant basic fibroblast growth factor in a
rabbit model of acute lower limb ischemia: dose-response effect
of basic fibroblast growth factor. J Vasc Surg. 1992;16:181–191.[Medline]
[Order article via Infotrieve]
-
Chlebourn JO, Martins RN, Mitchell CA, Chirila TV.
bFGF enhances the development of the collateral circulation after acute
arterial occlusion. Biochem Biophys Res Commun. 1992;185:510–516.[Medline]
[Order article via Infotrieve]
-
Battler A, Scheinowitz M, Bor A, Hasdai D, Vered Z,
DiSegni E, Varda-Bloom N, Nass D, Engelberg S, Eldar M, Belkin M,
Savion N. Intracoronary injection of basic fibroblast growth
factor enhances angiogenesis in infarcted swine myocardium.
J Am Coll Cardiol. 1993;22:2001–2006.[Abstract]
-
Harada K, Grossman W, Friedman M, Edelman ER, Prasad
PV, Keighley CS, Manning WJ, Sellke FW, Simons M. Basic fibroblast
growth factor improves myocardial function in chronically
ischemic porcine hearts. J Clin Invest. 1994;94:623–630.
-
Uchida Y, Yanagisawa-Miwa A, Ikuta M, Makamura F,
Tomaru T, Fujimori Y, Morita T. Angiogenic therapy of acute myocardial
infarction (AMI) by intrapericardial injection of basic fibroblast
growth factor (bFGF) and haparan sulfate (HS): an experimental study.
Circulation. 1994;90(suppl I):I-296. Abstract.
-
Unger EF, Banai S, Shou M, Lazarous DF, Jaklitsch MT,
Scheinowitz M, Correa R, Klingbeil C, Epstein SE. Basic fibroblast
growth factor enhances myocardial collateral flow in a canine model.
Am J Physiol. 1994;35:H1588–H1595.
-
Lazarous DF, Scheinowitz M, Shou M, Hodge E,
Rajanayagam MAS, Hunsberger S, Robinson G Jr, Stiber JA, Correa R,
Epstein SE, Unger EF. Effects of chronic systemic administration of
basic fibroblast growth factor on collateral development in the canine
heart. Circulation. 1995;91:145–153.
[Abstract/Free Full Text]
-
Barrios V, Cuevas B, Carceller F, Asin E,
Jiménez JJ, Navarro J, Garcia-Segovia J, Moya JL, Minguez I,
Cuevas P. Angiogenesis in the rat heart induced by local delivery of
basic fibroblast growth factor. Eur Heart J.
1995;16(suppl):171. Abstract.
-
Yang HT, Deschenes MR, Ogilvie RW, Terjung RL. Basic
fibroblast growth factor increases collateral blood flow in rats with
femoral arterial ligation. Circ Res. 1996;79:62–69.
[Abstract/Free Full Text]
-
Horrigan MCG, MacIsaac AI, Nicolini FA, Vince DG, Lee
P, Ellis SG, Topol EJ. Reduction of myocardial infarct size by basic
fibroblast growth factor after temporary coronary occlusion in
a canine model. Circulation. 1996;94:1927–1933.
[Abstract/Free Full Text]
-
Giordano FJ, Ping P, McKirnan MD, Nozaki S, DeMaria
AN, Dillmann WH, Mathieu-Costello O, Hammond K. Intracoronary
gene transfer of fibroblast growth factor-5 increases blood flow and
contractile function in an ischemic region of the heart.
Nat Med. 1996;2:534–539.[Medline]
[Order article via Infotrieve]
- Pepper MS, Ferrara N