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(Circulation. 2001;104:115.)
© 2001 American Heart Association, Inc.

Current Perspectives

Angiogenesis Therapy

Amidst the Hype, the Neglected Potential for Serious Side Effects

Stephen E. Epstein, MD; Ran Kornowski, MD; Shmuel Fuchs, MD; Harold F. Dvorak, MD

From the Cardiovascular Research Institute, MedStar Research Institute, Washington Hospital Center, Washington DC (S.E.E., R.K., S.F.) and Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass (H.F.D.).

Correspondence to Stephen E. Epstein, MD, Cardiovascular Research Institute, MedStar Research Institute, Washington Hospital Center, 110 Irving St NW, Suite 4B-1, Washington, DC 20010.

Key Words: angiogenesis • heart disease • cells • genes • growth substances

	Introduction

Top Introduction Aberrant Vascular Proliferation... Increased Vascular Permeability Induction of the Development... Triggering Growth of Neoplasms Increase in Atherosclerotic... Vasodilatation and Hypotension... Hazards Associated With Viral... Hazards Associated With Direct... Conclusions References

 
Although essentially unknown as a therapeutic concept as recently as a decade ago, it is difficult now to open a cardiology journal, attend a cardiology meeting, or scan a newspaper without being caught up in the excitement generated by the thought that angiogenesis therapy may soon have a major impact on the treatment of patients with atherosclerotic lesions obstructing arteries that supply the myocardium or legs. Potent therapeutic interventions, however, are rarely free of at least the potential for causing harmful effects. Angiogenesis therapy is no exception. Despite this and despite the fact that the only reasonably powered, randomized, double-blind clinical studies to date have failed to demonstrate primary end-point efficacy,¹ thoughtful consideration of the serious side effects that might accompany any therapeutic benefit has been largely missing from scientific communications.

For the lay media, a switch from this unbounded enthusiasm to profound skepticism occurred recently after a report of the tragic death of a young man caused by injection of large amounts of an adenoviral vector into the hepatic artery (unrelated to angiogenesis therapy).² For the scientific community, however, there has been a general lack of in-depth discussion of the potential dangers inherent in angiogenesis interventions. Such a discussion is appropriate not only because of the event cited above but also because considerable mechanistic data are available that actually permit us to identify specific side effects that we might anticipate as potential complications of angiogenesis therapy. The following therefore is a discussion of potential complications based predominantly on our knowledge of the underlying biological activities of 2 of the most potent angiogenic cytokines, vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF).

	Aberrant Vascular Proliferation in Nontargeted Tissues

Top Introduction Aberrant Vascular Proliferation... Increased Vascular Permeability Induction of the Development... Triggering Growth of Neoplasms Increase in Atherosclerotic... Vasodilatation and Hypotension... Hazards Associated With Viral... Hazards Associated With Direct... Conclusions References

 
Angiogenic agents are thought to have the potential to induce neovascularization in many different tissues. This becomes important in that under clinical circumstances it may not be possible to ensure that a therapeutic agent will be delivered exclusively to the target tissue for which it was intended. Therefore, an obvious potential complication is that an angiogenic agent will disseminate and induce unintended angiogenesis in adjacent and perhaps even in distant sites.

Mitigating this possibility, however, are data suggesting that angiogenesis will not occur in response to a cytokine unless a tissue has been appropriately "primed." Thus, although VEGF and its 2 major tyrosine kinase receptors, VEGFR-1 (flt-1) and VEGFR-2 (KDR/flk-1), are overexpressed in many malignant tumors and in other tissues undergoing active angiogenesis, most normal tissues do not express measurable levels of this ligand or its receptors or express them only at low levels.^{3 4} Therefore, it may be that aberrant neovascularization will not occur unless a normal tissue is exposed for prolonged periods to high doses of exogenously administered VEGF.

In contrast, both FGF and VEGF receptors are upregulated when tissues become ischemic^{4 5 6 7} ; therefore, ischemic tissue, the usual target of angiogenesis therapy, would be expected to respond more sensitively to the biological effects of FGF and VEGF than would normal tissues, a fact that would broaden the therapeutic window. This concept was supported by a study in which normal and ischemic canine myocardium was exposed to high local levels of FGF-1 (acidic FGF) protein administered via an epicardial sponge over a relatively prolonged time.⁸ Only ischemic myocardium responded with an angiogenic response, although the response was aberrant in that the newly formed vessels were hemangiomalike. Although the concept that there is a high threshold for neovascularization to develop in response to angiogenesis agents in normal tissues is reassuring, this consideration obviously does not apply to patients who have coexistent diseases, such as malignant tumors and in all probability diabetic retinopathy,^{9 10 11} conditions in which cytokine receptors are abnormally upregulated, thus rendering the tissues susceptible to neovascularization and disease progression.

	Increased Vascular Permeability

Top Introduction Aberrant Vascular Proliferation... Increased Vascular Permeability Induction of the Development... Triggering Growth of Neoplasms Increase in Atherosclerotic... Vasodilatation and Hypotension... Hazards Associated With Viral... Hazards Associated With Direct... Conclusions References

 
Although now most widely recognized as an angiogenic cytokine, VEGF was originally discovered in the course of investigations designed to identify the tumor-secreted factor responsible for the increased vascular permeability characteristic of nearly all malignant solid and ascites tumors.^{3 4 12 13 14 15 16 17 18} VEGF is one of the most potent vascular permeability factors known, rendering vessels hyperpermeable to circulating macromolecules at subnanomolar concentrations and with a potency some 50 000 times that of histamine.^{3 4 12 13 14 15 18 19} The onset of the vascular permeabilizing activity of VEGF is rapid, becoming evident within several minutes of injection. On the basis of this activity, it was first named vascular permeability factor.

It was only after these discoveries relating to vascular permeability that VEGF was also found to induce proliferation and migration of endothelial cells^{17 20 21 22 23} and to stimulate endothelial cell expression of matrix-degrading proteases, including plasminogen activators and collagenases.^{24 25} Each of these activities undoubtedly contributes to the potent in vivo angiogenesis effects of VEGF, which were later demonstrated.^{17 26 27}

Although these 2 major activities—increased vascular permeability and angiogenesis—could be viewed as subserving unrelated biological functions, a more likely view is that vascular permeability contributes importantly to the induction of angiogenesis.^{3 4 17 28} Numerous studies of angiogenesis as it occurs in such pathological and pathophysiological circumstances as tumors, wound healing, rheumatoid arthritis, and corpus luteum formation^{4 29 30 31 32} have consistently demonstrated that newly formed vessels are hyperpermeable and that increased vascular permeability not only accompanies but actually precedes angiogenesis.^{3 33 34 35}

The potent vascular permeability activity of VEGF, when expressed outside of its normal biological context (in which many concomitantly and sequentially active angiogenesis cofactors are present), is likely to have several undesirable consequences. First, extravasation of plasma and plasma proteins into the tissues triggers the clotting system,³⁵ leading to deposition of fibrin gel in the extravascular space. Like other gels, fibrin traps water and thus causes local edema. A recent report summarized the lower extremity edema-inducing effects of VEGF administered to patients with lower extremity ischemia. VEGF was administered as naked DNA encoding VEGF₁₆₅ either into the artery supplying the ischemic leg or intramuscularly. Transient edema was observed in 31 of 90 patients (34%), with 3 patients developing bilateral edema.³⁶ In addition to causing edema, fibrin gels are themselves both proangiogenic and prostromagenic and, when deposited in tissues, induce the influx of new blood vessels and fibroblasts, much as they do in tumors and healing wounds.^{28 37}

	Induction of the Development of Functionally Abnormal Blood Vessels

Top Introduction Aberrant Vascular Proliferation... Increased Vascular Permeability Induction of the Development... Triggering Growth of Neoplasms Increase in Atherosclerotic... Vasodilatation and Hypotension... Hazards Associated With Viral... Hazards Associated With Direct... Conclusions References

 
Another untoward consequence of VEGF therapy is that the newly formed vessels can be functionally abnormal. Administration of an adenoviral vector expressing murine VEGF₁₆₄ to adult mice induced an angiogenic response that was characterized by the formation of enlarged, thin-walled vessels that lacked supporting pericytes and were hyperpermeable to plasma proteins.³⁸ Such poorly formed vessels are common in tumors³⁹ and at early stages of wound healing.⁴⁰ Many of the progeny of these vessels were also abnormal and included glomeruloid vascular tangles of the type found in brain tumors and vascular malformations. In addition, the new vessels that VEGF induces, because of coexistent vascular hyperpermeability, develop in a fibrin-rich milieu of immature vascular connective tissue (granulation tissue),³⁸ raising the question of whether these vascular islands of granulation tissue, if they were to develop in ischemic tissue, would provide functional benefit.

Other serious functional consequences of VEGF administration were reported after intravenous injection into mice of an adenovirus carrying the VEGF transgene.⁴¹ Circulating levels of VEGF increased after system-wide increases in vascular permeability and multiorgan edema that led to the death of a high percentage of the animals. This study also demonstrated that pretreatment with an adenovirus carrying the angiopoietin-1 transgene prevented edema and death.

Taken together, these studies emphasize the fact that normal vessel development requires the expression and activity of multiple gene products⁴² ; therefore, it seems unlikely that overexpression of a single gene would induce the formation of structurally and functionally normal vessels.

	Triggering Growth of Neoplasms

Top Introduction Aberrant Vascular Proliferation... Increased Vascular Permeability Induction of the Development... Triggering Growth of Neoplasms Increase in Atherosclerotic... Vasodilatation and Hypotension... Hazards Associated With Viral... Hazards Associated With Direct... Conclusions References

 
The capacity of angiogenic agents to cause cellular proliferation could have an additional serious side effect—that of enhancing the growth of coexisting but unrecognized tumors. FGF is a promiscuous mitogen that stimulates proliferation of a wide variety of cell types and through this mechanism might stimulate tumor growth. VEGF, in contrast, acts primarily on vascular endothelium, cells that selectively express the 2 high-affinity VEGF receptor tyrosine kinases. Therefore, it might be postulated that VEGF lacks the capacity to increase proliferation of transformed neoplastic cells that are not of endothelial origin. Recently, however, a number of nonendothelial tumor cells have been found to possess low levels of functional VEGFR-1 and VEGFR-2.⁴³

Moreover, there is strong evidence that solid tumors require an angiogenic response to supply the nutrients required for growth beyond minimal size.⁴⁴ Induction of angiogenesis therefore provides an additional mechanism by which an angiogenic agent administered to treat tissue ischemia could trigger the growth of dormant or in situ tumors independently of any direct effects that the agent might have on tumor cell proliferation.

Finally, a third receptor for VEGF₁₆₅, neuropilin, has recently been discovered.⁴⁵ It is widely expressed by vascular endothelium and many other cells, including some tumor cells. Although VEGF-neuropilin interactions per se do not appear to induce angiogenesis, neuropilin does potentiate signaling mediated by the classic VEGF receptors and could have other effects on endothelium (or on other cells and tissues) that have not yet been appreciated.

The above comments relate to the possibility that angiogenic factors may stimulate the growth of an existing neoplasm. However, de novo tumor development is also a possibility, because it has been demonstrated experimentally that prolonged exposure of skeletal muscle or myocardium to high local levels of VEGF or FGF family peptides can cause hemangiomalike tumors and vascular malformations.^{8 38 46 47} Also, certain normal tissues, notably the uterus, possess functional VEGF receptor tyrosine kinases⁴⁸ ; in fact, VEGF is mitogenic for uterine smooth muscle. It is therefore possible that the common leiomyoma (fibroid) could at least theoretically respond to exogenous stimulation by growth factors.

Despite these potential mitogenic effects of angiogenesis interventions, it must be emphasized that even in the animal experimental studies demonstrating tumor development, there has been no evidence of malignant transformation. In addition, agents currently in clinical trials have passed an array of toxicological tests to the satisfaction of the FDA. So although some caution is warranted, a balanced view would at this time lead to the conclusion that it is unlikely that such agents, administered in the context of angiogenesis therapy, will lead to de novo tumor formation, will trigger the growth of any clinically silent neoplasms that may be present, or will cause their malignant transformation.

	Increase in Atherosclerotic Plaque Mass and Instability

Top Introduction Aberrant Vascular Proliferation... Increased Vascular Permeability Induction of the Development... Triggering Growth of Neoplasms Increase in Atherosclerotic... Vasodilatation and Hypotension... Hazards Associated With Viral... Hazards Associated With Direct... Conclusions References

 
The mechanisms by which VEGF and FGF family peptides have the potential to stimulate neoplastic growth are also relevant to their reported proatherogenic effects. Several studies have demonstrated that these agents are present in atherosclerotic plaques^{49 50} and that under various experimental circumstances their administration increases neointimal smooth muscle cell proliferation and neointimal mass.^{51 52 53 54} Also, many studies have demonstrated a large increase in the vasa vasorum that supply the neointima of both atherosclerotic and restenotic lesions, and it has been postulated that the nutrient blood flow provided by such vessels is necessary for lesion expansion.^{55 56 57 58 59} VEGF could contribute to these changes by stimulating angiogenesis either directly or indirectly by effecting the deposition in neointima of proangiogenic fibrin and fibrous connective tissue.^{3 4 28 37} Hence, there are several mechanisms by which delivery of VEGF or FGF to atherosclerotic vessels might promote lesion growth.

Administration of MCP-1 has recently been proposed as a strategy for enhancing collateral function through the remodeling of existing collaterals by the process of arteriogenesis.⁶⁰ The beneficial effects of MCP-1 demonstrated experimentally are believed to be caused by its ability to attract monocytes to the site of incipient arteriogenesis. Once in the subintimal space, monocytes differentiate into macrophages, which secrete various cytokines and growth factors that induce remodeling of existing small collaterals, thereby augmenting collateral function.^{61 62}

From the perspective of increasing flow to ischemic regions via collateral growth, these effects are desirable. But from the perspective of atherogenesis, the potential consequences of these events are a cause for concern. Activated macrophages resident within atherosclerotic lesions have profoundly deleterious effects on plaque evolution, including a putative role in plaque instability and rupture.⁶³ Insofar as either MCP-1 or VEGF, which also is a monocyte chemoattractant,^{64 65} increases the entry of monocytes into atherosclerotic vessels, their administration could lead to deleterious effects on the course of atherosclerosis.

	Vasodilatation and Hypotension During Short-Term Administration of FGF and VEGF Proteins

Top Introduction Aberrant Vascular Proliferation... Increased Vascular Permeability Induction of the Development... Triggering Growth of Neoplasms Increase in Atherosclerotic... Vasodilatation and Hypotension... Hazards Associated With Viral... Hazards Associated With Direct... Conclusions References

 
The FGF and VEGF families of growth factors can produce vasodilatation and hypotension when given rapidly, which appears to be caused, at least in part, through a nitric oxide–mediated pathway.^{66 67 68} The potential seriousness of this effect is evidenced by a study in which 4 of 8 pigs that had myocardial ischemia secondary to constriction of the circumflex coronary artery developed hypotension and died after the start of VEGF protein administration.⁶⁹ In addition, in a phase 1 study evaluating the safety of basic FGF administered into the coronary arteries of patients with coronary artery disease,⁷⁰ 1 patient developed prolonged hypotension. However, this complication occurred only at the highest dose of this dose-escalation study; in a subsequent phase 1 trial in which basic FGF was administered into the femoral artery of patients with claudication, none of the patients developed hypotension.⁷¹ It is likely that the hypotensive effects that develop after administration of VEGF or FGF proteins can be minimized with proper dosing and slow administration. Of course, this complication is of less concern when VEGF or the FGFs are administered as genes; the process of gene transcription and mRNA translation is slow enough that the equivalent of a bolus secretion of protein is unlikely, although not impossible.

	Hazards Associated With Viral Vectors

Top Introduction Aberrant Vascular Proliferation... Increased Vascular Permeability Induction of the Development... Triggering Growth of Neoplasms Increase in Atherosclerotic... Vasodilatation and Hypotension... Hazards Associated With Viral... Hazards Associated With Direct... Conclusions References

 
One of the common ways that potentially therapeutic transgenes are delivered to patients is through adenovirally mediated transfection of cells with replication-incompetent adenoviral vectors. Adenoviral vectors provide high levels of gene transfer and expression, but virus-related potential side effects, such as the induction of immune and inflammatory responses, are potential problems. Although it is unlikely that this will be a major problem given the doses of virus that are currently being administered in angiogenesis trials, it is another potential side effect that has to looked for in the large clinical trials that are being planned.

	Hazards Associated With Direct Myocardial Delivery

Top Introduction Aberrant Vascular Proliferation... Increased Vascular Permeability Induction of the Development... Triggering Growth of Neoplasms Increase in Atherosclerotic... Vasodilatation and Hypotension... Hazards Associated With Viral... Hazards Associated With Direct... Conclusions References

 
Recent studies have explored the feasibility and potential merits of minimally invasive modes for direct intramyocardial injection of angiogenesis factors compared with their infusion into the coronary arteries or their transepicardial administration during surgery.^{72 73} The use of catheter-based approaches for transendocardial injection of recombinant genes or growth factors to enhance myocardial angiogenesis may represent a novel approach to the treatment of ischemic cardiovascular disease. However, it should be recognized that the field of catheter-based transendocardial gene delivery is in its infancy and may harbor potential hazards as well. Currently, most catheter designs for transendocardial gene delivery either are crude or require sophisticated manipulation. Technical advances will probably lead to better catheter handling characteristics and will optimize needle stability in beating heart conditions so that minimal myocardial trauma results.

It should be noted that the very advantage of direct intramyocardial delivery—local expression of large amounts of angiogenesis proteins—could result in myocardial inflammation, fibrosis, and angioma formation. During the injection procedure, extreme shear forces could alter plasmid DNA or adenoviral vectors, resulting in impaired DNA integrity and functionality. Systemic distribution of transgene and secreted proteins may still occur even after direct intramyocardial gene delivery, especially with suboptimal injection techniques. Thus, systemic distribution, albeit minimized, may still be an issue for consideration after local angiogenic gene delivery.

	Conclusions

Top Introduction Aberrant Vascular Proliferation... Increased Vascular Permeability Induction of the Development... Triggering Growth of Neoplasms Increase in Atherosclerotic... Vasodilatation and Hypotension... Hazards Associated With Viral... Hazards Associated With Direct... Conclusions References

 
In conclusion, all angiogenic agents currently being tested have multiple potent biological activities that confer on them the capacity to stimulate the growth of new blood vessels. However, it is these very same biological effects that also have the potential to cause serious complications. It is to be hoped that strategies can be developed to deliver angiogenesis agents to target tissues with enough selectivity that nontargeted tissues are not aberrantly stimulated. In this regard, it does appear likely that ischemic tissues that would be expected to benefit from angiogenic intervention are more sensitive to the biological effects of the angiogenic cytokines than are most normal tissues, providing an additional margin of safety. This, of course, does not obviate the potential dangers posed by exposing possible coexisting abnormal angiogenesis-sensitive tissues, such as occult neoplasms, and other conditions in which angiogenesis plays a pathophysiological role, such as diabetic retinopathy.

We are optimistic that ultimately angiogenesis therapy will prove to be effective and safe. However, the above considerations emphasize the need to be aware of the biological effects of each angiogenic agent being proposed for clinical studies and to accept the likelihood that complications will occur. This awareness, coupled with a rigorous scientific analysis of carefully controlled large clinical trials, will lead to a more accurate assessment of the actual frequency with which these agents cause serious complications and thereby to a more valid risk versus benefit analysis of these novel, and potentially extremely important, therapeutic interventions.

	Acknowledgments

 
This work was supported by the US Public Health Service National Institutes of Health grants CA-50453 and HL-54465 and under the terms of a contract from the National Foundation for Cancer Research (Dr Dvorak).

	Footnotes

 
This research was supported in part by Biosense, maker of the Biosense Catheter system. Dr Epstein is a holder of a patent for the intracoronary administration of angiogenesis drugs and is a consultant for Shering-Berlex Pharmaceuticals, which is involved in angiogenesis studies.

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Top Introduction Aberrant Vascular Proliferation... Increased Vascular Permeability Induction of the Development... Triggering Growth of Neoplasms Increase in Atherosclerotic... Vasodilatation and Hypotension... Hazards Associated With Viral... Hazards Associated With Direct... Conclusions References

 
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