The discovery of the role of VEGF in retinal/choroidal neovascularization (CNV) and the subsequent development of VEGF antagonists to inhibit its activity were significant breakthroughs for treating neovascular eye diseases. Anti-VEGF therapies are widely used in the clinic to treat neovascular age-related macular degeneration (AMD) and, more recently, other proliferative vasculopathies. More potent and longer-lasting VEGF antagonists continue to be developed despite clear data from several groups working in multiple organ systems that VEGF also exerts critical potent vasculotrophic and neurotrophic effects. We recently reported that the targeted deletion of VEGF in adult murine retinal pigment epithelial (RPE) cells induces rapid and progressive vascular and neuronal cell atrophy in the retina. In this report, we will review the basic and clinical research reports that clearly demonstrate that endogenous VEGF in multiple tissues, including the retina, provides critical trophic support for neurons and vessels, and in the absence of this local, paracrine effect, there is significant anatomical and functional loss in the retina and other organ systems.
AMD & VEGF antagonism
In humans, phototransduction occurs in photoreceptors located in the outer retina; much of the metabolic ‘housekeeping’ related to this process is carried out by the underlying RPE cells. RPE cells also partition the neurosensory retina from the high-flow choriocapillaris and also perform multiple functions essential for choriocapillaris homeostasis. Death or dysfunction of RPE cells is characteristic of AMD, one of the leading causes of legal blindness in older people in industrialized countries. The central phenotypes of AMD are photoreceptor/RPE atrophy (the ‘dry’ or ‘atrophic’ form) and CNV (the ‘wet’ or ‘neovascular’ form).
The results of numerous studies have shown that VEGF drives neovascularization in different ocular disease models Citation[1–4]. Although the fundamental mechanisms of CNV initiation and maintenance in neovascular AMD are still unclear, it is clear that the contribution of VEGF to abnormal vascular proliferation and permeability is significant and inhibiting VEGF has a beneficial therapeutic effect. Pegaptanib (Macugen®, Eyetech Inc., FL, USA) was the first anti-VEGF drug approved to treat AMD Citation[5]. It is a therapeutic aptamer that specifically binds to VEGF165, an isoform of VEGF associated with pathological neovascularization Citation[6]. Later, ranibizumab (Lucentis®, Genentech, CA, USA), a Fab antibody fragment against VEGF, was developed and approved for clinical use Citation[7]. While the selectivity of pegaptanib for VEGF165 inhibition was expected to make it more effective and safe, the results of clinical trials showed that pan-VEGF isoform inhibitors such as ranibizumab were actually more effective Citation[8]. This observation also accelerated the development of more potent VEGF antagonists including, aflibercept (Eylea® or VEGF Trap-Eye, Regeneron Pharmaceuticals Inc., NY, USA), a recombinant fusion protein containing the extracellular domain of human VEGF receptor-1 and -2, which bind VEGF with 100-fold greater affinity than ranibizumab Citation[9]. Aflibercept was recently approved for the treatment of wet AMD.
Physiological requirements for VEGF in the retina
VEGF induces proliferation and migration of endothelial cells and enhances vascular permeability. The gene encoding VEGF is haplo-insufficient and mutations induce hypovascularity and embryonic lethality Citation[10,11]. In the eye, RPE cells synthesize and secrete VEGF vectorially toward the choriocapillaris; the loss of RPE-derived VEGF during embryogenesis induces pronounced developmental defects in the choriocapillaris atrophy Citation[12,13]. We have recently demonstrated that RPE-derived VEGF is also essential for maintenance of the choriocapillaris during adulthood. Using inducible targeted gene deletion technologies, we ablated the VEGF gene in the RPE of adult mice and observed rapid and irreversible choriocapillaris Citation[14]. Cone function was also profoundly diminished as evidenced by severely abnormal photopic and flicker electroretinograms. Severe choriocapillaris defects and photoreceptor degeneration are also observed in mice that lack the soluble VEGF isoform (VEGF188/188 mice) Citation[15]. Adenoviral, shRNA or neutralizing antibody-mediated inhibition of VEGF in the retina also induces significant neuronal cell death Citation[16–18]. Importantly, neurotrophic functions of VEGF have also been reported in other organ systems Citation[19,20]. Collectively, these findings indicate that basal levels of secreted RPE-derived VEGF are critical for normal retinal function.
Possible dangers of chronic VEGF antagonism
While most patients that receive VEGF antagonists do not appear to experience obvious adverse effects, no long-term evaluations have yet been performed. There is mounting evidence, however, that repeated intraocular VEGF antagonism may not be completely safe. The results of a small clinical trial demonstrate that patients receiving repeated doses of VEGF antagonists to treat neovascular AMD experienced a significant decrease in cone function Citation[21]. Furthermore, in two different large-scale clinical trials, increased occurrences of RPE/photoreceptor atrophy (characteristic of atrophic AMD) were observed in multiple patients after 2 years of repeated intraocular injections of VEGF antagonists Citation[22,23]. Chronic systemic VEGF antagonism for cancer treatment is associated with proteinuria and renal thrombotic microangiopathy Citation[24] since podocyte-derived VEGF is important for maintenance of the glomerular microvasculature Citation[25,26]. Gastrointestinal perforation, pulmonary hemorrhage and arterial thrombosis are infrequent but severe life-threatening events that are also associated with systemic VEGF antagonism Citation[27]. A more recent report demonstrates that VEGF antagonism may induce metabolic disease progression since adipocyte-derived VEGF critically restores metabolic homeostasis Citation[28].
In summary, these collected observations serve as a warning that potent, persistent VEGF antagonism may more effectively control neovascularization, but it may also increase the risk of off-target effects, including neuronal and vascular degenerations that can also lead to vision loss. To better assess these potential risks, we believe it will be important to follow selected cohorts of patients on chronic anti-VEGF therapy to assess progression of geographic atrophy (through direct observation and imaging technologies) and cone function (through electroretinography). We suggest that the use of synergistic, combination antiangiogenic therapies would permit the use of substantially lower levels of VEGF antagonists and, thus, may minimize the risk of off-target effects of VEGF inhibition.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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