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Angiogenesis Research Center, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215
AFTER INITIAL
EUPHORIA from early reports of successful therapeutic
angiogenesis induced by either application of growth factors or laser
revascularization in patients with peripheral and coronary disease,
recent reports from large well-controlled studies involving vascular
endothelial growth factor (VIVA) (15), basic
fibroblast growth factor (FIRST) (18), and transmyocardial
laser (DIRECT) (M. Leon, Transcatheter Cardiovascular Therapeutics 2000 meeting and American Heart Association 2000 presentations) have cast a pall on the field. In all of these trials, primary
end points have been solidly negative, although post hoc analysis
suggested some evidence of efficacy in various subgroups. This turn of
events calls for a reevaluation of current approaches to therapeutic angiogenesis, including underlying biological principals, choice of
angiogenic agents, validity and interpretation of animal model data and
translation of the animal data to clinical trials, and the means of
delivery. Equally important issues surrounding organization, conduct,
and interpretation of clinical trials in this field are beyond the
scope of this editorial and the reader is referred to a recent review
of this subject (44).
Two major events, occurring either separately or in combination,
are responsible for a majority of cases of tissues ischemia: compromise of the proximal arterial blood supply or of the distal runoff. The former event is the principal cause of ischemia
associated with coronary artery disease when a complete or partial
occlusion of the major epicardial coronary arteries or their principal
branches results in insufficient blood supply to the distal myocardial bed, as well as intermittent claudications in patients with peripheral vascular disease. The latter event, diffuse narrowing of small vessels
resulting in poor blood runoff from a proximal conduit, is a major
contributor (in addition to the proximal arterial disease) to tissue
ischemia and gangrene as well as failure of bypass grafts in
patients with diabetic peripheral vascular disease. The primary focus
of a therapeutic intervention in the former case should be to
reestablish the arterial inflow, whereas in the latter to improve the
distal runoff. Arguably, the restoration of arterial inflow requires
the stimulation of growth of conduit vessels capable of carrying
significant blood flow, i.e., true "biological bypasses," a process
termed arteriogenesis (4, 5). In contrast, stimulation of
the distal runoff may be promoted by increasing venous capillary formation (a process termed true angiogenesis) in the ischemic bed and, perhaps, lymphatic vessels.
Emerging data indicate that these processes respond to different
stimuli and are regulated by different growth factors. Thus shear
stress, increased local expression of leukocyte adhesion molecules, and
the influx of blood-derived white blood cells are the primary
arteriogenic stimuli (4, 38). The predominant growth
factors involved are fibroblast growth factors (FGF), platelet-derived growth factor, and perhaps other monocyte/macrophage-derived products (1, 16, 26, 52). At the same time, ischemia is the
major stimulus of true angiogenesis. Low tissue oxygenation, perhaps via alterations in the cellular redox balance (8, 12),
increases expression of the hypoxia-induced factor (HIF)-1 As the preceding section illustrates, the choice of an angiogenic
agent is one area that merits reevaluation. VEGF is perhaps the most
extensively studied growth factor. Among its many interesting features
is a unique sensitivity of the developing vasculature to the amount of
VEGF165 isoform, with even 50% reduction in the protein
levels leading to embryonic lethality (7, 10). Recent studies have drawn a link between the hypoxia-induced VEGF expression by circulating monocytes and the extent of collateral development in
patients with coronary artery disease (39).
Functional roles of other VEGFs including VEGF121 and
VEGF-B and C (VEGF-2) have not been as well defined (31,
32). In vitro VEGF121 is significantly less
effective then VEGF165 in activation of flk-1 receptor,
whereas VEGF-C appears to be primarily involved in lymphatic vessel
development. These and other differences aside, all VEGFs are weak
mitogens and their primarily endothelial site of action may not be
ideal in situations when arteriogenesis is the desired goal.
At the opposite end of the growth factor scale are FGFs, another
extensively studied growth factor family. In contrast to VEGF, FGFs are
potent mitogens capable of stimulating growth of a large number of cell
types (45). At the same time, disruptions of FGF-1
(30) and -2 (53) genes have little impact on
the mouse embryonic development or adult phenotype. In part, this may
reflect a large redundancy in the FGF family and in part the defects,
such as decrease in vascular tree branching, may be rather subtle.
Despite these profound differences, VEGF and FGF2 share a common
feature in the current generation of therapeutic angiogenesis trials:
the failure to induce functional benefit when administered in a
relatively nonselective fashion. Whether these findings reflect the
inability of individual growth factors to orchestrate the entire
spectrum of events required for growth of new blood vessels or attest
to the difficulty with local delivery and/or clinical trial design and
execution in this field remains unclear.
One intriguing concept is the use of angiogenesis "master switch"
genes, i.e., genes capable of inducing entire cascades of angiogenesis-related genes. The best studied example of such a gene is
a transcription factor HIF-1 The validity of animal models used for preclinical testing of
angiogenic growth factors and laser myocardial revascularization (LMR)
is an important question. Indeed, studies in small animals (mice,
rabbits) (6, 24, 33, 46, 50, 51) and in large animals
(dogs, pigs) (21, 28, 41, 48, 49) suggested that both VEGF
and FGF2 induce functionally significant angiogenesis after single
bolus delivery or intramyocardial gene injections. However, there are a
number of important differences between these animal models and the
patients enrolled in clinical trials. One such difference is that the
animals do not have atherosclerotic vascular disease. The presence of
such disease may adversely affect response to growth factors. Another
key difference is age. Whereas a typical patient in these trials is
old, a typical animal in a preclinical study is usually a young adult
or is still growing. A limited amount of data suggests that
responsiveness to angiogenic therapy decreases with age (34,
35). One more important caveat is that a number of commonly used
medications can potentially interfere with angiogenic response
(17, 29). The final, and perhaps the most important,
difference is that laboratory animals represent an unselected
population, whereas a typical patient in therapeutic angiogenesis
trials has been selected because of demonstrated failure to develop
adequate collateral circulation and/or respond to prior therapeutic
interventions (the "no option" patient). All of these factors
combined suggest that a lack of response in a large animal study should
translate into a lack of response in a clinical trial, whereas a
positive animal study does not guarantee a positive outcome in a trial.
Indeed, several observations seem to bear out these conclusions.
Intravenous infusion of VEGF was not effective in a pig Ameroid model,
whereas an intracoronary infusion of 0.25 µg · kg The effective delivery of the angiogenic agent, be it a gene or a
protein, has been perhaps the biggest and, until recently, the least
appreciated challenge. In general, systemic administration of
angiogenic proteins results in low concentration at the desired site
and carries a potential for significant systemic toxicity. Thus, in the
case of FGF2, both intracoronary and intravenous infusions result in
minimal (<1%) deposition and very short (half-maximal times ~6 h)
retention of the growth factor in the myocardium (22).
Alternatives to systemic administration include various forms of local
delivery and the use of "trigger" agents that would be active only
at the desired angiogenic site. Among various forms of local delivery,
intrapericardial infusion is somewhat more effective but impractical in
clinical settings (21). Intramyocardial injection of
proteins, whereas more effective in terms of efficiency of delivery and
the growth factor retention (19), is yet to be shown to
produce functionally significant improvement in perfusion and function
of the ischemic myocardial bed. Given these delivery problems,
the use of agents with a restricted mode of action is potentially
particularly interesting. One example of such molecule is a hormone
relaxin that is reported to stimulate angiogenesis at wound sites (due
to local stimulation of growth factor synthesis) but not healthy tissue
after systemic administration (47). This hormone, however,
also appears to have a systemic hypotensive effect by as yet undefined
mechanism (40).
Gene transfer to the myocardium by means of intramyocardial injections
has been used as an alternative strategy to achieve prolonged local
expression of angiogenic proteins. Whereas detailed analysis of this
technology is beyond the scope of this review, it is sufficient to note
that the observed protein expression is variable and cannot currently
be effectively regulated.
Another strategy designed to stimulate angiogenesis has involved the
use of LMR. Once the initial hope that the laser channels remain open
(thereby providing alternative source of arterial blood to the
myocardium) has been shown to be false, much excitement centered on
anatomical demonstration of local production of growth factors and the
appearance of sprouting capillaries at sites of laser injury. This is
expected, however, in any tissue healing response
(3). Indeed, it was never convincingly
demonstrated in a chronic ischemia animal model that laser
injury results in a measurable improvement in tissue perfusion and
function, and a recently completed double-blind controlled study of
catheter-based laser revascularization (DIRECT trial) showed no benefit
with regard to all tested end points.
Furthermore, ischemic tissues usually show a very significant
increase in VEGF (2, 14) and other growth factors
expression (9), and it is not clear why administration (or
stimulation of local production) of small amounts of additional protein
in the same territory should prove to be physiologically effective unless other mechanisms, unrelated to direct angiogenic effect of the
growth factor, are at play.
Taking all of these observations together, there is little rigorous
data to support the concept of physiological significant angiogenesis
by stimulation of intramyocardial production of growth factors either
by means of protein administration, gene transfer, or laser injury.
Given the appeal of arteriogenesis as the primary biological modality
for treatment of patients with coronary artery disease, epicardial
perivascular delivery at the site of where this process actually takes
place is theoretically most attractive.
The systemic (or nonselective) administration of the growth factors in
addition to not being particularly effective, likely carries some
risks. Furthermore, the amount of the growth factor delivered is
limited by its systemic side effects. For example, in the case of
VEGF165, a physiologically "effective" dose in pigs
resulted in 50% mortality from severe hypotension (13). A
smaller dose, still physiologically effective but less lethal in pigs
(28), was still above the minimally tolerated level that
could be achieved in a human trial. In this context, the failure of
intracoronary VEGF165 programs speaks not so much to lack
of effectiveness of the growth factor as to the lack of adequate dosing. In the case of FGF2, systemic dose-limiting side effects include hypotension, proliferative membranous nephropathy, and central
nervous system toxicity (18, 20).
In summary, therapeutic angiogenesis still remains a most intriguing
concept in cardiovascular medicine. A wealth of basic and animal data
indicate the biological feasibility of this approach. However, we still
have little experience in translating this kind of biological knowledge
into practical clinical tools. Perhaps our greatest challenge is to
rigorously define what we do not know to make a successful practical
transition. Whereas the rush to clinical trials was probably
premature, these initial failures have defined the issues that will
need to be overcome for angiogenesis to become a practical clinical
tool. Our ability to successfully address these challenges
while further advancing the underlying basic vascular molecular biology
and maintaining realistic expectations about the therapeutic prospects
will go a long way to implementing a major advance in basic research as
a practical clinical tool.
INTRODUCTION
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BIOLOGICAL FOUNDATION OF THERAPEUTIC ANGIOGENESIS
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protein
that in turn activates expression of vascular endothelial growth factor (VEGF), its receptors flt-1 and neuropilin-1, and angiopoietin-2 (Ang-2) (42, 43). Yet despite these clear differences
between the two processes, none of the angiogenesis trails carried out to date attempted to tailor the therapeutic approach to the desired biological effect whether in terms of growth factor selection or the
site of administration.
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. Because of its ability to activate a
number of genes involved in VEGF-dependent angiogenesis, this factor
may be particularly effective in situations where the stimulation of
capillary-venular growth is the major goal (for example, poor distal
runoff). It is not clear, however, how effective HIF-1 is in the
induction of arteriogenic response. Another interesting prospect is the
peptide PR39 (26). In addition to increasing HIF-1
protein levels, the peptide also induces expression of FGF receptors R1
and syndecan-4 (11, 25, 26). The ability to activate both
VEGF (via HIF-1) and FGF (via FGFR1 and syndecan-4) systems may be
particularly effective. Finally, relaxin is another protein capable of
increasing expression of both VEGF and FGF isoforms (see below).
Clinical utility of these proteins is clearly very appealing. However,
their testing to date in animal and/or clinical studies has been
minimal and many questions remain. Furthermore, there are likely other
similarly centrally positioned angiogenic control genes.
ANIMAL MODELS OF THERAPEUTIC ANGIOGENESIS
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1 · min1 was
minimally effective (36). Therefore, it is not surprising that a dose of 0.05 µg · kg1 · min1 given by
a combination of intracoronary and intravenous infusions was
ineffective in the VIVA trial (15). At the same time, 2 µg/kg ic FGF2 was the minimally effective dose in this model
(37). In the FIRST trial, 0.3 µg/kg ic dose was
ineffective, whereas 3.0 µg/kg ic had hints of efficacy
(18). Finally, local delivery of FGF2 using heparin
alginate microspheres was effective both in the Ameroid pig model
(27) and in a small double-blind randomized clinical trial
(23).
DELIVERY OF THERAPEUTIC AGENTS: LOCATION, LOCATION, LOCATION
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ACKNOWLEDGEMENTS |
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This paper was supported in part by National Heart, Lung, and Blood Institute Grants R01-HL-62289 and HL-53793 and P50 HL-63609 and the Established Investigator Award of the American Heart Association
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FOOTNOTES |
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* A precipice before, wolves behind.
Address for reprint requests and other correspondence: Michael Simons, Angiogenesis Research Center, RW-453 Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215 (E-mail: msimons{at}caregroup.harvard.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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