Wet AMD: anti-VEGF treatments in the elderly population

In 1971 Folkman proposed that tumour growth was dependent upon angiogenesis, and consequently suggested that preventing angiogenesis might prevent tumour growth.1 This concept led to research into manipulating angiogenesis in order to influence tumour progression, and subsequently other therapeutic areas, including cardiology and ophthalmology. In 1983 vascular permeability factor (VPF) was discovered, followed by vascular endothelial growth factor (VEGF) in 1989. It later transpired that they were in fact the same molecule.

Effect of VEGF on the vasculature

VEGF plays a primarily protective role in the vasculature (figure 1).² It is known that VEGF stimulation of the endothelium has an antithrombotic effect. It stimulates endothelial cells to proliferate and migrate, which is crucial for the renewal of the endothelium. VEGF also has an anti-apoptotic effect, allowing endothelial cells to survive for longer periods of time. VEGF stimulation of endothelial cells is involved in the induction and release of nitric oxide and prostacyclin, enabling the endothelial cells to interact with other cells.^3,4 Furthermore, VEGF has an antiproliferative effect on smooth muscle cells and regulates vessel wall permeability.⁵ It is therefore clear that inhibition of VEGF is likely to have unwanted effects on the vasculature: it would be prothrombotic, pro-apoptotic and vasoconstrictive.

Endothelial cells have a major role in angiogenesis. However, circulating monocytes also carry VEGF receptors and contribute to the formation of collateral vessels. In the heart and peripheral circulation, collateral vessels are protective, for example by providing additional tissue perfusion in the presence of blood vessel blockage. Indeed, VEGF stimulation can be used therapeutically to promote the growth of collateral vessels.⁶ If the femoral artery of a mouse is ligated (to induce claudication), perfusion can be significantly increased following the intravenous application of VEGF for seven days.⁷ Furthermore, this elevated perfusion appears to be largely mediated via VEGF receptor 1 (VEGFR-1), which is present on the surface of both endothelial cells as well as circulating monocytes.

A number of phase II and III trials of therapeutic angiogenesis have been conducted, many using VEGF receptor-stimulating agents, but with mixed results (table 1).^8-17 Consequently, there is no currently accepted pro-VEGF therapy with proven efficacy in the clinical situation. It is thought that a reason for treatment failure may have been the relatively short timeframe of VEGF application: in order for VEGF to exert a biological effect on collateral vessel growth, it needs to be present for at least one week in sufficient concentrations. All the therapies trialled so far have resulted in only a short spike in VEGF concentration. With improvement of the duration of VEGF receptor stimulation, better results might be seen.

In the presence of ischaemia, VEGF levels rise, suggesting that hypoxia stimulates the VEGF system (figure 2).¹⁸ However, VEGF also appears to be present in non-ischaemic tissue, suggesting that a baseline level of VEGF is required to maintain normal vascular function. Reduction in this baseline level of VEGF is likely to result in adverse effects on the circulatory system.

There are a number of different strategies that can be utilised to inhibit VEGF signalling. These include: anti-VEGF antibodies, soluble VEGF receptors, aptamers, VEGF receptor antibodies and inhibitors of the VEGF receptor signalling pathway (tyrosine kinase inhibitors).^19,20

Effects of VEGF on the lung

VEGF inhibition has been used for the treatment of various cancers.²¹ An interesting finding from the treatment of lung cancer is that a baseline level of VEGF activity appears to be required for the maintenance of normal lung function. Following the introduction of a VEGF receptor-inhibiting agent, lung cell apoptosis has been seen to occur.²² Thus, inhibition of VEGF could lead to emphysema and lung destruction.

Effects of VEGF on atherosclerosis

A number of factors are known to be present within atherosclerotic plaques that stimulate the development and growth of plaques. Among these is VEGF. It has been proposed that, in the atherosclerotic plaque, VEGF stimulates endothelial proliferation and migration, leading to an increase in plaque angiogenesis, matrix degradation and immature vessels and resulting in plaque instability. In turn, plaque instability can lead to thrombotic events, including myocardial infarction and ischaemic stroke. However, it is also possible that VEGF could provide an increase in plaque stability by decreasing endothelial cell apoptosis and improving endothelial cell function, resulting in the prevention of vascular regression (figure 3).

In trials where VEGF was added to atherosclerotic plaques, no evidence for further progression of the plaque or evidence of increased instability has been observed.^23-25 However, extrapolation from oncological findings predicts that inhibiting VEGF would result in capillary regression, capillary thrombosis and intraplaque necrosis (figure 4). This would lead to an increase in thrombotic events in those receiving VEGF-inhibiting therapy.

The age-related macular degeneration population

Coronary atherosclerosis is a frequent finding in the elderly population, and the risk of coronary atherosclerosis rises with age. The one-day mortality of acute myocardial infarction is around 35%.²⁶ The one-year mortality of patients above 75 years of age with ST-elevation myocardial infarction (STEMI) is 52.4% for conservative treatment and 19.2% for primary percutaneous intervention.²⁷

At the time of diagnosis of age-related macular degeneration (AMD), the average patient is 75 years of age, with a life expectancy of 11.8 years.^28,29 Neovascular AMD (wet AMD) is often associated with significant co-morbidities, such as diabetes and cardiovascular disease.³⁰ Wet AMD may be treated with VEGF inhibitors, which, although administered intravitreally, are absorbed systemically and thus could potentially have systemic effects.

Summary

Angiogenic growth factors are important functional stimuli for vascular cells. As well as stimulating angiogenesis, they are involved in maintenance of the integrity of the vasculature. Inhibition of angiogenic growth factors efficiently inhibits tumour angiogenesis and reduces tumour growth. However, inhibition of angiogenic growth factors may lead to vascular dysfunction and vascular complications such as atherosclerotic plaque rupture and acute ischaemic syndromes.

This should be an important consideration when administering VEGF-inhibiting treatment for wet AMD, in a population that is already at high risk for cardiovascular events.

Conflict of interest
Professor Waltenberger is an advisor to Pfizer.

References

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