Vascular Biology |
From the Department of Medicine (I.Z., A.M., J.M.), University College London, London, UK, and A.I. Virtanen Institute and Department of Medicine (S.Y.-H.), University of Kuopio, Kuopio, Finland.
Correspondence to Dr Ian Zachary, Department of Medicine, University College London, 5 University St, London WC1E 6JJ, UK. E-mail I.Zachary{at}ucl.ac.uk
| Abstract |
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Key Words: angiogenesis atherosclerotic prostacyclin nitric oxide endothelium
| Introduction |
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| Effects of VEGF in the Cardiovascular System |
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Because hypoxia is a stimulus for VEGF production, it is probable that endogenous collateral vessel formation in the ischemic heart could occur through sprouting angiogenesis from preexisting vessels mediated by locally produced VEGF. An important new insight into the mechanism through which VEGF can stimulate neovascularization in adults has come from the discovery of circulating endothelial progenitor cells (also called angioblasts) and the illumination of the role played by these cells in VEGF-driven postnatal vasculogenesis and angiogenesis.29 30 31 These findings not only add an important new facet, as well as further complexity, to the mechanisms of postnatal blood vessel formation, but importantly, they also broaden the scope of therapeutic angiogenesis to embrace strategies based on cell delivery as well as cytokine therapy. The use of endothelial progenitor cells further enlarges the range of therapeutic options because they can be genetically engineered to express proangiogenic cytokines or other therapeutically useful molecules.
Clearly, these studies offer enormous potential for the therapeutic use of VEGF. Nevertheless, there are several outstanding problems that proponents of VEGF therapy need to consider and that are likely to modify our understanding of the role of VEGF in cardiovascular disease and practical approaches in using VEGF as a therapeutic cytokine. These problems can be summarized under the following headings: (1) risks associated with unwanted angiogenesis, (2) uncertainty concerning the sufficiency of VEGF for arteriogenesis and viable collateral formation, and (3) the preliminary nature of the studies performed so far in humans.
| Risks of Unwanted Neovascularization |
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| Is VEGF Sufficient for Collateral Artery Formation? |
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A more fundamental reason why VEGF may be insufficient for collateral formation is that angiogenesis (the sprouting of capillaries) is a process different from the proliferation of preexisting arteriolar networks to produce collateral arteries, a process called arteriogenesis. Thus, it can be argued that whereas new microvessels induced by exogenous VEGF provide a limited and short-term palliative to ischemic heart tissue, only the formation of true collaterals constitutes an effective therapeutic strategy. An important insight into the mechanism of arteriogenesis is the finding that monocyte activation plays a major role in angiogenesis and collateral artery formation.41 42 However, because VEGF promotes monocyte chemotaxis,43 it is plausible that VEGF could still be a key orchestrator of arteriogenesis by stimulating monocyte recruitment. At present, it seems that judgment as to whether VEGF is sufficient to trigger an arteriogenic (as distinct from an angiogenic) response is suspended. Even if VEGF can initiate arteriogenesis, it is nevertheless becoming increasingly apparent that other cooperating factors and receptor-mediated mechanisms are required for different stages in the development of mature vascular networks. Tie receptors and their ligands, the angiopoietins, and other factors, such as platelet-derived growth factor, are crucial for sprouting angiogenesis, for the recruitment of vascular smooth muscle cells (SMCs), and for the pruning and stabilization of blood vessels in the later stages of angiogenesis.2 44 Such remodeling may be essential for the formation of mature viable collateral vessels.
| Results of Studies of Therapeutic Angiogenesis in Humans |
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Although VEGF alone may not be sufficient for inducing a viable therapeutic angiogenic response, this cytokine is able to regulate a spectrum of biological processes, including hypotension and vasorelaxation in mature adult vascular beds in vivo, effects that may play important roles in regulating vascular function.20 48 49 VEGF is well known to increase vascular permeability, and this could play an important pathophysiological role in angiogenic disease, including many ocular neovascularizing disorders and some tumors, both of which are often associated with severe edema.50 51 In the remainder of the present review, we consider how recent work on the biological actions of VEGF is generating novel insight into the mechanisms by which this cytokine can protect the arterial wall against disease.
| Vascular Protection |
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We and other investigators have established that VEGF is able to augment several endothelial cell functions, including NO and prostacyclin (PGI2) production,8 48 55 56 57 58 59 which may be implicated in VEGF-dependent endothelium-mediated protective vascular effects.8 VEGF induces NO production and cGMP accumulation in endothelial cell cultures55 56 57 and stimulates PGI2 production via mitogen-activated protein kinasedependent activation of cytosolic phospholipase A2.58 NO production induced by VEGF probably involves activation of the constitutive eNOS isoform. This may occur in part by VEGF-induced Ca2+ mobilization,60 61 in common with other activators of eNOS. Another mechanism for VEGF-dependent NO synthase activation may be through activation of the heat shock protein Hsp 90 or an Hsp 90associated protein.62 Activation of Hsp 90 seems to increase its affinity for and association with eNOS to stimulate eNOS activity.
What are the likely biological consequences of VEGF-induced NO and PGI2 production? An important function of these 2 intercellular mediators is vasodilatation, but NO and PGI2 have several other effects that may perform vascular protective roles, including the inhibition of SMC proliferation, antiplatelet actions, and, in the case of NO, inhibition of leukocyte adhesion.
Antimitogenic effects of NO and PGI2 on SMCs have been demonstrated in vitro and in vivo and act via the production of the intracellular messengers cGMP and cAMP, respectively.63 64 65 66 67 68 Clinical application of PGI2 has been frustrated by the failure of short-term PGI2 administration to inhibit restenosis after balloon injury and by the intolerable side effects of high PGI2 doses.69 70 Recently, however, gene transfer of PGI synthase was shown to accelerate reendothelialization and to reduce neointimal formation after balloon injury.71 eNOS gene transfer also reduces neointimal hyperplasia in balloon injury models of restenosis.64 72 Inhibition of neointimal SMC hyperplasia after VEGF delivery in the rabbit collared carotid artery or balloon denudation and stent implantation may be mediated in part through the antimitogenic effects of these 2 intercellular mediators.
Another important vascular protective effect of NO and
PGI2 that is predictable from in vitro studies is
the inhibition of platelet aggregation and, hence, an
antithrombotic effect.73 74 There is no direct evidence so
far that VEGF is antithrombotic, but some findings are very suggestive.
VEGF increases the expression and activation of the serine proteases,
urokinase and tissue-type plasminogen
activator, which cleave plasminogen to generate
the key thrombolytic enzyme, plasmin.75 In
vivo studies of vascular effects of VEGF have provided no evidence that
VEGF increases the risk of thrombus formation, and 4 studies have
demonstrated that VEGF delivery markedly reduces mural thrombus
formation after balloon injuryinduced intimal
thickening.9 10 11 12 Paradoxically, VEGF induces the secretion
of von Willebrand factor (vWF)58 76 and the
expression of tissue factor43 in human umbilical vein
endothelial cells, effects that, in contrast to NO and
PGI2, could play a role in thrombogenesis. vWF
plays a crucial role in the adhesion of platelets to
subendothelial collagen,77 and tissue
factor expression and activation are essential for the extrinsic
pathway of coagulation and clot formation.78 However, VEGF
appears only to increase the surface expression of active tissue factor
on endothelial cells in cooperation with tumor necrosis
factor-
.79 Other findings may point toward a role for
vWF and tissue factor in angiogenic functions of VEGF. Mice deficient
in tissue factor have an impaired pattern of extraembryonic
angiogenesis during embryogenesis,80 81 and vWF increases
endothelial cell adhesion, suggestive of a role in the
maintenance of endothelial
integrity.82 Interestingly, VEGF is released by
platelets, its synthesis is increased by thrombopoietin in
megakaryocytic cell lines, and increased levels of VEGF are found at
the site of hemostatic plugs in humans.83 84 85 It remains
enigmatic whether VEGF plays a regulatory role in platelet function
and thrombosis, and this is a potentially important aspect of the in
vivo action of VEGF that needs to be addressed.
A further key component in a vascular protective function of VEGF-induced NO production is likely to be the ability of NO to inhibit leukocyte recruitment to blood vessels.86 It is now well established that endogenous NO synthesis inhibits leukocyte rolling and adhesion as well as the upregulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1.86 87 Given the important role played by adhesion molecule expression and leukocyte adhesion in the early stages of atherosclerosis, VEGF-induced NO synthesis might be predicted to have antiatherogenic properties.
PGI2 and, particularly, NO are short-lived intercellular mediators, and if they play a role in the long-term protective effects of VEGF, it is likely that mechanisms might exist for increasing the effective longevity of the signal. In the case of NO, an insight into how production of NO might be prolonged has come from the finding that VEGF can increase the expression of eNOS.8 88 89
Another important mechanism through which VEGF may augment
endothelial function is by increasing
endothelial cell survival
(Figure
). VEGF was originally shown to
act as a survival factor for retinal endothelial
cells.90 More recently, VEGF has been reported to inhibit
human umbilical vein endothelial cell apoptosis
by activating the antiapoptotic Akt/PKB pathway via a
phosphatidylinositol 3'-kinasedependent pathway.91 92
VEGF also increases tyrosine phosphorylation and the
focal adhesion association of focal adhesion kinase (FAK) and the
FAK-associated protein paxillin.93 Because FAK appears to
be critical for maintaining survival signals in adherent cells and
because in endothelial cells, FAK tyrosine
dephosphorylation (M. Lobo, I. Zachary, unpublished
data, 1999) and caspase-mediated proteolytic cleavage are early
responses to apoptogenic stimuli,94 95 96 97 it is possible
that VEGF-dependent survival signaling may also be relayed through
increased FAK tyrosine phosphorylation.
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The receptor mediating VEGF-induced NO and PGI2 production in human umbilical vein endothelial cells is likely to be KDR (VEGF receptor-2) because this is the major receptor for VEGF in these cells, and PlGF, a specific ligand for the high-affinity Flt-1 receptor (VEGF receptor-1), had no effect on these biological functions.43 58 98 Whether KDR is the receptor that mediates the arterioprotective functions of VEGF in vivo or whether there is a role for Flt-1 and the putative recently identified KDR coreceptor, neuropilin-1,99 100 is currently being investigated. Other VEGF-related cytokines, (VEGF-B, -C, and -D and PlGF),1 100 101 102 103 could also play a role in cardiovascular protective functions either therapeutically or physiologically depending on the expression profiles for different VEGF receptors in cardiovascular tissues. VEGF-C has been shown to be angiogenic in the rabbit ischemic hindlimb model,104 and our recent unpublished data show that VEGF-C gene transfer can accelerate reendothelialization and inhibit intimal hyperplasia in the balloon-injured rabbit aorta (M.O. Hiltunen, K. Alitalo, S. Yla-Herttuala, et al, unpublished data, 1999). It is not yet clear whether vascular endothelial effects of VEGF-C are mediated via KDR or Flt-4 (VEGF receptor-3).
An intriguing speculation that arises from these findings is whether
VEGF functions as an endogenous vascular protective factor.
The ability of VEGF to induce NO and PGI2
production, increase endothelial integrity and
survival, and inhibit intimal SMC proliferation makes it a particularly
attractive candidate for such a role. SMCs produce VEGF in response to
hypoxia, growth factors, and cytokines (see
Figure
).105 106 107 Intimal thickening and plaque
formation are associated with increased production of growth
factors and cytokines and may cause reduced oxygen tension in
medial SMCs by increasing the diffusion distance of oxygen from the
lumen. Therefore, the atherosclerotic milieu may promote
endogenous VEGF synthesis, and in agreement with this
hypothesis, VEGF expression has been demonstrated in atherosclerotic
lesions.108 109 Reduced expression or impaired function of
VEGF would, in turn, be predicted to attenuate
endothelial antiproliferative and antithrombotic
functions and, hence, encourage SMC proliferation and promote
atherogenesis.
The notion of vascular protection emphasizes the consequences of VEGF biological functions for the cardiovascular system that are not readily predictable from the perspective of therapeutic angiogenesis. However, the discussion of the ramifications of VEGF-mediated biological actions for thrombosis highlighted the difficulty of integrating these diverse actions into the vascular protection model. It is also likely that the context, in terms of pathophysiology, tissue type, and the cytokine milieu, will be crucial for determining the overall outcome of VEGF treatment. In turn, this suggests that VEGF may even have deleterious as well as beneficial consequences for the cardiovascular system depending on the site of action, the specific type of disease or therapeutic intervention (eg, bypass graft or angioplasty) being targeted, and the presence of other cooperating cytokines. Thus, VEGF delivered locally to the site of anastomosis in a bypass graft may reduce the risk of stenosis, whereas VEGF within an existing atherosclerotic plaque could have the contradictory effects of enhancing endothelium-dependent protective functions on one hand and inducing neovascularization on the other. These suppositions indicate that the careful selection of the pathophysiological context in which VEGF is delivered to patients and the need for targeted delivery are likely to be crucial for ensuring successful VEGF therapy.
| Feasibility of Local Human VEGF Gene Transfer |
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Preliminary results have described the beneficial effects of nontargeted VEGF gene transfer in human peripheral vascular disease and ischemic myocardium.26 28 The feasibility of local VEGF gene therapy in humans was studied by using an infusion-perfusion catheter to transfer VEGF plasmid to human coronary arteries immediately after angioplasty in 15 patients with angina pectoris that was due to a single lesion in 1 coronary artery.46 47 The results showed that 1000 µg of VEGF plasmid cDNA was well tolerated. Systemic leakage of the VEGF transgene was minimal, as judged by polymerase chain reaction, but in a patient with critical leg ischemia subjected to the same gene transfer procedure, VEGF transgene expression could be detected in peripheral tibial artery segments up to 180 days after angioplasty.47 Arterial pieces distal and proximal to the site of angioplasty did not express the transgene, indicating minimal lateral diffusion of the VEGF plasmid. Mouse VEGF was used in that study (Laitinen et al47 ) to allow detection of any increase in VEGF protein specifically arising from gene transfer. Mouse VEGF could not be detected in the systemic circulation by specific ELISA, indicating minimal systemic leakage of transduced protein. Laitinen et al show that local VEGF transfer is feasible, safe, and well tolerated. The failure to detect VEGF protein systemically could indicate either that expression is truly local or that expression is very low. However, long-term low-level expression may be sufficient to achieve beneficial effects locally without raising systemic VEGF protein levels sufficiently to promote angiogenesis at distant sites.
| Conclusions and Perspectives |
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From a therapeutic standpoint, the vascular protection paradigm may have the greatest relevance for pathophysiological contexts in which stenosis occurs in previously normal vessels characterized by relatively undamaged or undiseased endothelia. Theoretically, clinical situations that could be suitable for local extravascular VEGF gene delivery are bypass grafting, tissue transplantation, and access for renal dialysis arteriovenous access loops. In all these situations, a major cause of nonacute failure is stenosis of a previously unoccluded vessel at or near the anastomosis. An additional important feature of these clinical procedures is that they allow perivascular surgical access and are therefore potentially useful for local extravascular VEGF gene therapy.
The potential for using VEGF therapy in cardiovascular diseases is an exciting one, but effectively harnessing this potential clearly poses challenges for scientists and clinicians alike. In meeting these challenges, an improved understanding of how this multifunctional cytokine works, one that fully encompasses the complexity of VEGF biology, is essential. The concept of VEGF-directed vascular protection may add an important new dimension to this understanding.
| Acknowledgments |
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Received August 26, 1999; accepted November 30, 1999.
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