See related article, pages 779 –786
The Putative Convergent and Divergent Natures of
Angiogenesis and Arteriogenesis
Volkhard Lindner, Thomas Maciag
T
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nous VEGF contribute directly to arteriogenesis. These investigators report that the levels of endogenous VEGF and its
high-affinity receptors, VEGFR1 and VEGFR2, as well as
HIF1␣ and metabolic indicators of ischemia were similar in
skeletal muscle of rabbit hind legs in the presence or absence
of femoral artery ligation. Further analysis using hemodynamic methods demonstrated that the continuous infusion of
VEGF did not improve collateral formation, yet the administration of monocyte chemotactic protein-1 (MCP1) significantly improved collateral conductance.10 Because mononuclear cells are well described as a source of the prototype
members of the FGF gene family,11,12 it is reasonable to
suggest that mononuclear cell infiltration of ischemic tissue
may be an important contributor to arteriogenesis. The ability
of FGF to be released into the extracellular compartment in
response to cellular stress13 and tissue injury14 is consistent
with this premise and, as a result, may provide the requisite
mitogenic potential for arteriogenesis as a late response
signal. Thus, we suggest that in response to tissue ischemia,
VEGF gene expression may be responsible for mediating the
immediate-early angiogenic response whereas MCP1 and/or
other members of the CC and CXC chemokine families may
facilitate the initiation of the mid-to-late response by the
recruitment of mononuclear cells for the delivery of FGF as
a mediator of the mid-to-late arteriogenic response.15,16 Because this hypothesis requires the presence of a signal that
limits the angiogenic activity of VEGF, it is anticipated that
a dominant-negative effector(s) of VEGF signaling may be
present during the initiation of the mid-to-late MCP1 response. Although the nature of these dominant-negative
effectors is not known, it is possible that this may include the
expression of alternatively spliced forms of the VEGFR
transcripts encoding the extracellular domains of these receptors that are known to function as dominant-negative effectors of VEGF-mediated signaling.17
The hydrolytic remodeling of the extracellular matrix, as
well as the expression and function of cell fate determination
genes, may be additional important components of the
immediate-early angiogenic response and mid-to-late arteriogenic responses because these components may contain
additional temporal and divergent features responsible for
regulating the on-site activities of VEGFs, the CC and CXC
chemokines, and FGFs, including the functions of the glycosylaminoglycans. For the successful development of any
angiogenic or arteriogenic therapy, it is important to consider
that the on-site delivery of these hormonal signals may be a
key feature for their ability to integrate and cooperate with
other on-site receptor-mediated signaling pathways. Indeed,
the relatively short half-life that most polypeptide growth
factors exhibit in the circulatory system after bolus intravas-
he postnatal function of blood vessels is determined
by the physiology of individual tissues and organs as
well as the size and mass of an individual species, and
a corollary to this premise is the suggestion that not all blood
vessels are created equal. Postnatally, new blood vessel
growth occurs either by angiogenesis or arteriogenesis, and
thus, it is anticipated that the mechanisms responsible for
these processes will exhibit convergent and divergent features.1 Because angiogenesis involves the coordinated migration, proliferation, and differentiation of endothelial cells
(ECs) and pericytes from existing vascular beds and arteriogenesis, the growth of muscular arteries, requires similar
events regulated by ECs and smooth muscle cells (SMCs)
from preexisting arteries, it is anticipated that these cells will
have evolved divergent mechanisms responsible for their
postnatal development and growth.2,3 Indeed, a recent study
by Hershey et al4 examined the relationship between angiogenesis and arteriogenesis in the development of functional
collateral blood vessels in the rabbit ischemic hind limb
model and observed that although capillary sprouting via
angiogenesis occurred as an early response to tissue ischemia,
improved collateral blood flow occurred only as a late
response when arteriogenesis could be demonstrated using
angiographic methods. These data suggest that a temporal
relationship may exist between angiogenesis and arteriogenesis in which the angiogenic component precedes the arteriogenic component in the formation of a collateral vasculature
visualized by angiographic methods.
The angiogenesis factor, VEGF, is well described as a
rapidly induced hypoxia-response gene.5 If angiogenesis and
arteriogenesis were not temporally related, it is likely that the
mechanisms responsible for the angiogenic and arteriogenic
responses may both be due to the function of enhanced VEGF
expression and VEGF receptor–mediated signaling because
the expression of VEGF is an immediate and rapid event.
However, a direct role for VEGF in the angiogenic component of arteriogenesis has been quite controversial.6 –9 In this
issue of Circulation Research, Deindl et al10 provide direct
experimental evidence that neither endogenous nor exogeThe opinions expressed in this editorial are not necessarily those of the
editors or of the American Heart Association.
From the Center for Molecular Medicine, Maine Medical Center
Research Institute, Scarborough, Maine and the Center for Biophysical
Sciences, University of Maine, Orono, Maine.
Correspondence to Thomas Maciag, Center for Molecular Medicine,
Maine Medical Center Research Institute, 81 Research Dr, Scarborough,
ME 04074. E-mail [email protected]
(Circ Res. 2001;89:747-749.)
© 2001 American Heart Association, Inc.
Circulation Research is available at http://www.circresaha.org
DOI: 10.1161/hh2101.099662
747
748
Circulation Research
October 26, 2001
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cular administration18,19 should be a significant concern for
design of any future therapeutic protocol because the inability
to achieve sufficiently high levels of the polypeptide growth
factor in the appropriate target tissue is unlikely. Whether the
continuous local delivery of any polypeptide growth factor
using an osmotic pump, a gene therapy strategy, or an
alternative approach actually results in a net increase in the
levels of the polypeptide growth factor within the target tissue
should be clarified by preclinical studies. Indeed, the inability
to achieve critical on-site levels of polypeptide growth factors
in a target tissue after bolus intravenous injection may have
been the major reason for the disappointing results of the
clinical trials using VEGF and the major reason for the
success of the FGF prototypes to augment human collateral
blood vessel growth following the direct cardiac injection of
the polypeptides.20,21
Although the results of Deindl et al10 argue that VEGF may
not directly promote the growth of collateral arteries, it is
likely that VEGF may still contribute to arteriogenesis since
VEGF is indeed a potent stimulator of angiogenesis and an
angiogenic response precedes arteriogenesis. One might anticipate that with the growth of new capillaries, the demand
for blood flow may be expected to increase in the artery
feeding the capillary bed. In order to maintain a constant level
of shear stress, the artery should undergo positive remodeling, which requires arterial growth.22 Indeed, it is highly
likely that in the absence of angiogenesis, there may be
limited, if any, arteriogenesis. Because increases in arterial
blood flow have been shown to induce remodeling in association with arterial growth in the absence of an ischemic
situation, a known mediator of VEGF gene expression, it is
also possible that the function of VEGF may be attenuated by
receptor-dependant mechanisms including the expression of
dominant-negative forms of VEGFR through combinatorial
splicing or repression of specific VEGFR gene expression. In
our own arteriogenic studies, we observed significant expression of the VEGFR1 transcript in migrating and proliferating
ECs,23 yet we were unable to detect the presence of the
VEGFR2 transcript, which has been shown to be important in
mediating the mitogenic activity of VEGF. Although arterial
EC were able to respond to infused VEGF with an increase in
vascular permeability, we failed to observe an increase in
either EC proliferation or endothelial outgrowth.23 Likewise,
VEGFR1 is also expressed in neointimal SMCs, but these
cells do not respond to VEGF as a mitogenic signal.24 In
contrast, the infusion of FGF2 into these arteries resulted in
significant increases in EC and SMC proliferation.25,26
Expression of MCP1 in the presence of adhering monocytes/macrophages has been observed in proliferating endothelium and smooth muscle,27,28 and the observation by
Deindl et al10 that MCP1 was able to function as a mediator
of arteriogenesis is quite interesting in that regard because it
enables one to anticipate the function of other polypeptide
cytokines that are known to be modifiers of EC and SMC
migration, growth, and differentiation. Perhaps most notable
are the members of the IL gene family and CXC chemokine
family, which are known to function as EC cytokines.29,30
Indeed, it will be interesting to determine whether these
proinflammatory EC cytokines can function to substitute for
MCP1 and modify arteriogenesis or whether MCP1 is able to
regulate the expression of either members of the IL gene
family or other proinflammatory cytokine genes.
Acknowledgements
This work was supported by NIH Grants AG98503, HL35627, and
HL32348 (to T.M.) and RR15555 (to V.L. and T.M.).
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KEY WORDS: fibroblast growth factor 䡲 hypoxia 䡲 monocyte chemotactic
protein-1 䡲 stress 䡲 vascular endothelial growth factor
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The Putative Convergent and Divergent Natures of Angiogenesis and Arteriogenesis
Volkhard Lindner and Thomas Maciag
Downloaded from http://circres.ahajournals.org/ by guest on June 16, 2017
Circ Res. 2001;89:747-749
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