(Circulation. 1995;91:2699-2702.)
© 1995 American Heart Association, Inc.
Articles |
Growth Factor Therapies for Vascular Injury and Ischemia
From the Cardiology Division, University of Texas Medical School at Houston; Hermann Hospital; and Texas Heart Institute (Houston).
Correspondence to Ward Casscells, MD, Texas Heart Institute, MC 2-255, PO Box 20345, Houston, TX 77225-0345.
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Introduction |
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 Top Introduction References |
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In this issue of Circulation, Asahara et al1 report that reendothelialization of the rat carotid artery after balloon denudation is accelerated by a local 30-minute incubation of 100 µg of vascular endothelial growth factor (VEGF 165). This treatment also may have increased the final extent of reendothelialization by
50%, although the 4-week end point is too
early to be certain. Recently, Callow et al2 reported
equally dramatic effects using twice-weekly intravenous doses of 100
µg in the rabbit. Although no toxicity was described in the rabbit
studies, the present report by Asahara and colleagues suggests that
a single local administration is efficacious, eliminating concerns
about other potential in vivo effects of VEGF, including
vasorelaxation3 and increased vascular
permeability.4 These outcomes were by no means guaranteed, since there was no previous evidence that VEGF played a role in this process. VEGF, a glycoprotein that is mitogenic for endothelial cells and angiogenic in vivo, is known to be expressed in ischemic and hypoxic myocytes5 6 and tumor cells (and indeed, the VEGF and erythropoietin genes have similar hypoxia-responsive regulatory regions7 ), but injured arteries are not hypoxic. VEGF is made by smooth muscle cells, and it may prove to be upregulated after balloon injury, since in other cells its expression is induced by protein kinase C and by tissue factor,8 which are activated after balloon injury.
These studies are also noteworthy for the magnitude of the effects, which contrast with reports that growth factors only marginally enhance dermal wound healing in normal animals (in contrast to the considerable enhancement of wound healing by growth factors in old or diabetic animals or in infected wounds).9 Thus, the results might be even more dramatic in "problem wounds."
Is restenosis a "problem wound"? Coronary restenosis causes little or no increase in mortality but a substantial increase in morbidity (angina, myocardial infarction, repeat angioplasty, and aortocoronary bypass surgery) and consequent expense.10 Endothelial regeneration is probably delayed or eventually incomplete in many patients with restenosis. Even in young, rapidly healing animals, extensive balloon injury often fails to reendothelialize completely.11 Human evidence is sketchy: follow-up is incomplete and biased; moreover, the lack of endothelial cells in atherectomy specimens could reflect dislodgment of endothelial cells by the catheter (for review see Reference 1212 ). Postmortem studies may also be unrepresentative, and only that of Gravanis and Roubin13 systematically sought evidence for endothelial cells. They did not find them at the angioplasty site in patients who died within 1 month of percutaneous transluminal coronary angioplasty (PTCA) but found substantial reendothelialization in the later specimens.
The second finding of the present study is also noteworthy: reendothelialization in VEGF-treated vessels was associated with less neointimal accumulation and a wider lumen. This result may seem obvious, since it is well known that endothelial cells can release substances that (1) inhibit thrombosis, leukocyte attachment, and growth; (2) cause vasorelaxation to numerous agonists by elaboration of nitric oxide (NO), prostacyclin, prostaglandin E2 (PGE2), and perhaps atrial natriuretic peptides14 ; and (3) mediate remodeling.15 In some models of vascular injury, however, the reendothelialized portions of the vessel developed more neointima than the nonreendothelialized portions,16 exhibited vasoconstrictor responses to agonists such as acetylcholine and thrombin, and were somewhat thrombogenic.17 The atherogenic effect of injured or regenerating endothelium was probably due to increased endothelial production of fibroblast growth factors (FGFs), epidermal growth factor, platelet-derived growth factors (PDGFs), transforming growth factor-ß1 (TGF-ß1), insulin-like growth factor 1 (IGF-1), fibronectin, thrombospondin, endothelin, and other mitogens for smooth muscle cells and/or to decreased production of heparin-like molecules and NO.12 In these studies, the mature response (vasodilation, antithrombosis, and inhibition of smooth muscle cells) was not observed until weeks after endothelial regeneration was complete.17 Indeed, high doses of VEGF can apparently exacerbate the formation of a neointima.18 Since VEGF is an endothelium-specific mitogen—and indeed, its known classes of receptors are found only on endothelial cells—this result must reflect some indirect action, such as the enhancement of permeability by VEGF: extravasation of fibrinogen and thrombin into the vessel wall would be expected to result in thrombosis, inflammation, and mitogenesis.
Such caveats must be kept in mind but should not delay final preclinical studies, since the negative effects appear to be dose dependent. Indeed, Isner and Feldman19 have already administered the VEGF gene to a patient with peripheral arterial insufficiency.
The most important animal study that should be undertaken before a clinical trial to enhance reendothelialization after balloon angioplasty is the replication of these results in an atherosclerotic pig or canine model (the latter being partially but not completely resistant to atherosclerosis), ideally using middle-aged or old animals and including careful toxicity studies looking for vascular leakiness (particularly in the brain); thrombosis; hypotension; decreased myocardial contractility; chronotropic effects; and effects on bone marrow, liver, and kidney function.
Reasonable clinical indications would be recurrent thrombosis or restenosis after PTCA or peripheral angioplasty in patients with life-threatening myocardial or peripheral ischemia who are at high risk for bypass procedures and who have no known malignancy. Ideally, clinical studies should include not only the standard measures of restenosis such as minimal lumen diameter, percent diameter stenosis, lumen loss, and evidence of ischemia but also measures of endothelial function, such as coronary artery and microvascular vasodilation to mediators such as acetylcholine, measured by quantitative coronary angiography and Doppler flow wire.20 21
Clinical trials of VEGF to promote reendothelialization will probably reveal marked variability in the control group and in the treatment group, since experimental studies indicate that many variables influence reendothelialization. These include (1) the extent of denudation; (2) the presence of branches, which can serve as sources of regenerating endothelial cells; and (3) plaque morphology, which may affect local shear forces. These variables may explain the lesion-to-lesion independence of restenosis rates within the same individual.22
Other variables likely to contribute to the outcome include those
associated with impaired endothelial migration and/or proliferation:
old age, oxidized LDL, angiotensin II, TGF-ß, interleukin (IL)-1ß,
tumor necrosis factor-
, interferon-
, leukemia inhibitory factor,
platelet factor 4, serotonin, plasminogen activator inhibitor 1,
hyperglycemia, uremia, and use of ticlopidine (see References 1212 and
2323 ). Variables likely to be associated with faster or more complete
endothelial regeneration include laminar flow, high levels of HDL,
IGF-1, plasminogen activators, magnesium, estrogens, IL-4, and
hepatocyte growth factor. Variables that can enhance or
retard reendothelialization (depending on their concentration and the
type of model studied) include fibronectin, norepinephrine, heparin,
NO, PDGF-BB, and PGE2 (see Reference 1212 ).
Factors that can profoundly enhance endothelial regrowth in an autocrine and paracrine fashion and that circulate briefly after tissue injury include basic FGF (FGF-2) and acidic FGF (FGF-1).24 Conversely, the plasminogen fragment angiostatin is inhibitory,25 and the matrix glycoprotein thrombospondin usually inhibits endothelial cell growth, migration, and angiogenesis.26
It is likely that even with VEGF therapy, endothelial regrowth will proceed at suboptimal rates in some patients, particularly those with a deficiency or defect in VEGF receptors or those in whom endothelial regrowth is inhibited at some "downstream" step. The mechanisms of endothelial regeneration are notably complex (see References 1212 , 2424 , and 2727 ). The process begins 2 to 4 hours after denudation, with endothelial spreading and migration. DNA synthesis begins at 12 to 16 hours. Migration may contribute to subsequent DNA synthesis by traction on adjacent arterial cells or by the loss of contact inhibition. Migration persists even if DNA synthesis is prevented, and while many factors are both chemoattractant and mitogenic for endothelial cells, such as FGF-1, FGF-2, and VEGF, others stimulate one but not the other.12
Migration involves repetitive polymerization and disassembly of actin filaments anchored to regions of the plasma membrane known as focal contacts. These regions integrate signals mediated by integrins, cadherins, growth factor receptors, and seven-membrane-spanning, G protein–coupled receptors. Subsequent phosphoinositide hydrolysis, calcium transients, and protein interactions regulated by tyrosine phosphorylation and dephosphorylation lead to ATP-dependent contraction of actin filaments against myosin 2, resulting in ameboid movement.27 Contacts between the cell and the collagen substratum are mediated by fibronectins, laminins, and other glycoproteins. Forward movement requires spatially and temporally regulated attachment and detachment, mediated by plasminogen activators (for reviews see References 1212 , 2323 , 2828 , and 2929 ). If VEGF therapy alone proves insufficient, it can certainly be combined with FGF-2—a combination that has proved synergistic in in vitro studies30 —or with HDL, estrogens, IGF-1, heparin, converting enzyme inhibitors, and so forth. Eventually, any beneficial effect will have to compete with other promising therapies for restenosis, which include irradiation, smooth-muscle toxins, antisense oligonucleotides to signaling and cell-cycle molecules, and gene therapy for overproduction of NO and prostacyclin (for reviews see References 1212 and 3131 through 3332 33 ) and of VEGF itself.
The success reported for VEGF in enhancing reendothelialization invites comparison with similar results obtained for FGF-134 and FGF-235 in the same model. The study with FGF-2 also described some neointimal thickening, consistent with the mitogenic effect of FGF-2 for smooth muscle cells in vitro. Since FGF-1 also has this in vitro property, the lack of neointimal thickening with systemic administration of FGF-1 in the same model is somewhat surprising and may reflect different dosing regimens.
Acidic and basic FGFs are, like VEGF, heparin-binding polypeptides that are mitogenic and chemotactic for endothelial cells in culture and are angiogenic and vasodilating in vivo.36 37 The two FGFs differ from VEGF in that they are synthesized in large amounts by endothelial cells (particularly FGF-2), act on a wide variety of cell types, and have a number of nonmitogenic functions, although no VEGF-like effect on permeability or recruitment of inflammatory cells has been reported. Knockouts of these genes have yet to be reported.
The two FGFs also differ from VEGF in a number of biochemical properties, including the facts that they are nonglycosylated, have no signal peptide, can be found in the nucleus, are transcribed by alternative translation sites from a single mRNA transcript, and can function as monomers. In most systems, endothelial cell migration proliferation and angiogenesis have been accelerated by exogenous FGF-2 and inhibited by neutralizing antibodies or antisense oligonucleotides to FGF-2. Unlike VEGF mRNA, FGF-2 transcripts are not reported to be upregulated by hypoxia, but FGF-2 is released from cellular and extracellular storage sites by hypoxia and physical injury,38 39 as well as by nonlethal exposure to heat, pressure, heparin, several cytokines, and certain enzymes, including thrombin, plasmin, cathepsin G, complement C5b-9, and phospholipase-A (see References 3636 and 4040 ). Clearly, it would be worth looking for additive or synergistic effects on reendothelialization after balloon injury.
Other potential applications for VEGF, FGF-2, and possibly FGF-1 include (1) the enhancement of myocardial and peripheral angiogenesis, for which there is growing evidence of benefit41 42 43 44 (although the creation of new leaky vessels in the plaque could conceivably predispose to plaque rupture); (2) the reendothelialization of advanced atherosclerotic plaques, many of which show focal denudation45 ; (3) the reversal of endothelial cell senescence (which may predispose to thrombosis), an effect already demonstrated for FGF-246 (but not yet for VEGF) in cultured endothelial cells; (4) healing of myocardial infarction; (5) recanalization of thrombus; and (6) advanced congestive heart failure, which is characterized by microvascular dysfunction perhaps due to circulating cytokines, which can injure or kill endothelial cells.47
One or more of these properties may contribute to the beneficial effects described in a second article in this issue of Circulation: Bauters et al48 ligated the external iliac artery and excised the ipsilateral femoral artery in rabbits and measured flow velocity in the internal iliac artery at rest and in response to serotonin and acetylcholine. At 10 days, half of the animals received a single administration of VEGF 165. Thirty days later, resting flows, peak velocities, and arterial diameters were identical in the two groups, but the arteries in the group that received VEGF vasodilated to acetylcholine and did not vasoconstrict in response to serotonin. The flow response to nitroglycerin was also greater in the group that had received VEGF, suggesting a larger vascular tree. Presumably, this reflected the angiogenic effect of VEGF. The authors did not assess capillary density or endothelial DNA synthesis. The improved endothelium-dependent function is probably a result of the acceleration of the angiogenic process: collaterals developing in response to ischemia are prone to vasoconstriction, requiring many weeks to reach physiological maturity.49 Assessments at later time points would probably have shown very similar results in the two groups.
The possibility that VEGF exerted some other beneficial action cannot be excluded. For example, if the administered VEGF were bound and slowly released, it could have exerted a chronic vasodilating effect and led to flow-dependent remodeling. If VEGF shares some of the ability of FGF-2 to prolong cell survival under hypoxic or ischemic conditions,50 51 then this too could have contributed. However, the VEGF was administered at 10 days, by which time angiogenesis and collateral development were well under way.
The mechanism of the endothelium-dependent effects of VEGF is likewise unclear, since no attempt was made to block NO synthase, NO, or prostanoid production or to assess endothelial responsiveness to L-arginine or a calcium ionophore. Nevertheless, the effect is promising and may not yet be optimized. Together with recent demonstrations that VEGF,51 52 FGF-2,43 and FGF-144 promote peripheral and myocardial collateral development and improve endothelium-dependent vasorelaxation,52 these reports suggest that we are on the verge of a new era in cardiovascular medicine.
Received April 7, 1995; accepted April 8, 1995.
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References |
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TopIntroductionReferences |
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