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. 2021 Nov 1;62(14):26.
doi: 10.1167/iovs.62.14.26.

Retinal and Choroidal Vascular Diseases: Past, Present, and Future: The 2021 Proctor Lecture

Peter A Campochiaro  1
Affiliations

Retinal and Choroidal Vascular Diseases: Past, Present, and Future: The 2021 Proctor Lecture

Peter A Campochiaro. Invest Ophthalmol Vis Sci. .
No abstract available

PubMed Disclaimer

Conflict of interest statement

Disclosure: P.A. Campochiaro, Aerpio Pharmaceuticals (C); Allegro (C, I); Asclepix Therapeutics (C); Ashvattha Therapeutics (C, F); Bausch & Lomb (C); Clearside (C); Exonate Ltd (C); Genentech/Roche Inc (C, F); Graybug Vision (C, I); Gyroscope Therapeutics (C); Mallinckrodt Pharmaceuticals (F); Merck & Co Inc (C); Perfuse (C); Oxford Biomedica (F); Regeneron Pharmaceuticals (C); RegenxBio Inc (F); Sanofi Genzyme (F); Wave Life Sciences (C)

Figures

Figure 1.
Figure 1.
Molecular pathogenesis of ischemic retinopathies. Damage to retinal vessels results in decreased perfusion and retinal hypoxia causing stabilization of HIF-1. Increased levels of HIF-1 in the inner retina cause increased expression of multiple vasoactive factors and their receptors. The most important stimulator of retinal NV and excessive vascular leakage leading to macular edema is VEGF-A, but other VEGF family members, including VEGF-C and -D, which can stimulate VEGF receptor 2 (VEGFR2), and placental growth factor and VEGF-B, which stimulate VEGF receptor-1 (VEGFR1) may also contribute. Angiopoietin-2 (Angpt2) and vascular endothelial–protein tyrosine phosphatase (VE-PTP) inhibit Tie2, which decreases its stabilizing effect on endothelial cells, making them more responsive to VEGF family members. Recruitment of bone marrow–derived cells provides additional vasoactive stimulators and promotes leukostasis, which can further compromise perfusion. This recruitment occurs because leukocytes contain CXCR4, the receptor for stromal-derived factor-1 (SDF-1), and VEGFR1, which is activated by VEGF-A, VEGF-B, and placental growth factor. Activated endothelial cells release platelet-derived growth factor-B (PDGF-B) which recruits pericytes, glial cells, and RPE, which promote scarring.
Figure 2.
Figure 2.
Molecular pathogenesis of nAMD. HIF-1 is stabilized by oxidative stress and hypoxia, and both have been implicated in nAMD. Complement activation on choriocapillaris (CC) has been shown to cause CC drop out and hypoxia in the RPE and outer retina. Bruch's membrane is compromised by focal and diffuse deposits. Increased levels of HIF-1 in the outer retina and RPE cause increased expression of the same vasoactive factors and their receptors as seen in ischemic retinopathies. The most important stimulator of growth and leakiness of types 1, 2, and 3 CNV is vascular endothelial growth factor-A (VEGF-A), but other VEGF family members including VEGF-C and -D which can stimulate VEGF receptor 2 (VEGFR2), and placental growth factor and VEGF-B which stimulate VEGF receptor-1 (VEGFR1) may also contribute. Angiopoietin-2 (Angpt2) and vascular endothelial–protein tyrosine phosphatase (VE-PTP) inhibit Tie2, which decreases its stabilizing effect on endothelial cells, making them more responsive to VEGF family members. The recruitment of bone marrow–derived cells provides additional vasoactive stimulators. This recruitment occurs because leukocytes contain CXCR4, the receptor for stromal-derived factor-1 (SDF-1), and VEGFR1, which is activated by VEGF-A, VEGF-B, and placental growth factor. Activated endothelial cells release platelet-derived growth factor-B (PDGF-B), which recruits pericytes, glial cells, and RPE, which promotes subretinal fibrosis.
Figure 3.
Figure 3.
Role of VEGF-A in the progression of diabetic retinopathy. Hyperglycemia results in high glucose in the retina that, over a long period of time, causes damage to pericytes and endothelial cells of retinal vessels resulting in closure of retinal vessels. The slowly progressive retinal nonperfusion (RNP) eventually causes sufficient retinal hypoxia to stabilize HIF-1 increasing expression of VEGF-A then put the arrow and VEGF-A in parenthesis ↑VEGF-A and other hypoxia-regulated gene products. Once increased expression of VEGF occurs, it becomes the driver of the disease causing it to accelerate because it stimulates leukostasis causing progression of RNP further increasing VEGF expression (↑↑VEGF), resulting in a positive feedback loop for disease progression. Frequent anti–VEGF injections can interrupt the positive feedback loop by suppressing leukostasis thereby slowing progression of RNP and improving retinopathy. Reprinted with permission from Campochiaro PA, Akhlaq A. Sustained suppression of VEGF for treatment of retinal/choroidal vascular diseases. Prog Retin Eye Res. 2021;83:100921. Copyright © 2020 Elsevier Ltd.
Figure 4.
Figure 4.
Role of VEGF-A in progression of retinopathy due to RVO. RVO causes increased resistance in the retinal circulation. If there is little or no preexistent arterial disease, the increased resistance causes decreased blood flow and some retinal hypoxia, but little retinal nonperfusion (RNP) and modest increase in VEGF-A expression. The increase in VEGF results in macular edema, but it is easily controlled with anti–VEGF injections and after a moderate number of VEGF injections, they may no longer be needed. This course is common in young patients who on average have less retinal arterial disease than older patients. If there is substantial preexistent retinal arterial disease, the increased resistance from RVO results in closure of many capillaries and small arterioles which causes substantial increase in VEGF expression. The high levels of VEGF become the driver of the disease by stimulating leukostasis causing progression of RNP and further increasing VEGF expression (↑↑VEGF), resulting in a positive feedback loop for disease progression. If untreated or insufficiently treated, there is a poor outcome. Frequent anti-VEGF injections suppress leukostasis which decreases the progression of RNP and often causes it to improve. Some patients may eventually stabilize and no longer require injections, but the majority require long-term anti–VEGF injections to prevent the worsening of RNP and to suppress macular edema, which can result in a good visual outcome. Reprinted with permission from Campochiaro PA, Akhlaq A. Sustained suppression of VEGF for treatment of retinal/choroidal vascular diseases. Prog Retin Eye Res. 2021;83:100921. Copyright © 2020 Elsevier Ltd.
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