Growth-Modulatory Factors
The physical and chemical properties of the aqueous humor play a substantial role in modulating the proliferation, differentiation, functional viability, and wound healing of ocular tissues. These properties are largely influenced by several growth-promoting and differentiation factors that have been identified or quantified in aqueous humor, including the following:
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transforming growth factor βs 1 and 2 (TGF-β1 and -β2)
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acidic and basic fibroblast growth factors (aFGF and bFGF)
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insulin-like growth factor I (IGF-I)
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insulin-like growth factor binding proteins (IGFBPs)
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vascular endothelial growth factors (VEGFs)
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transferrin
The growth factors in the aqueous humor perform diverse, synergistic, and sometimes opposite biological activities. Normally, the lack of significant mitosis of the corneal endothelium and trabecular meshwork in vivo is probably controlled by the complex coordination of effects and interactions among the different growth-modulatory substances present in the aqueous humor (see Part V, Ocular Pharmacology).
Disruption in the balance among various growth factors, which occurs with the production of plasmoid aqueous humor as a result of breakdown of the blood–aqueous barrier, may explain the abnormal hyperplastic response of the lens epithelium and corneal endothelium observed in chronic inflammatory conditions and traumatic insults to the eye. Ultimately, however, the effect of a given growth factor on the aqueous humor is determined primarily by the growth factor’s bioavailability. Bioavailability, in turn, depends on many factors, including the expression of receptors on target tissues, interactive effects of the growth factor with components of the extracellular matrix, and the levels of circulating and matrix-bound proteases.
Growth factor levels in the aqueous humor are altered in several disease states. Levels of IGFBPs are elevated fivefold in patients with diabetes mellitus without retinopathy, and IGF-I levels are elevated in patients with diabetic retinopathy. VEGF levels in the aqueous humor are elevated in eyes with acute nonarteritic ischemic optic neuropathy, whereas interleukin-2 concentration is reduced.
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Micieli JA, Lam C, Najem K, Margolin EA. Aqueous humor cytokines in patients with acute nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol. 2017;177:175–181.
Vascular endothelial growth factors
The VEGF family of glycoproteins includes VEGF-A, -B, -C, and -D, as well as placental growth factor (PlGF). VEGF-A, the most thoroughly studied at present, has 9 isoforms and is the only VEGF family member induced by hypoxia. VEGF-A is a crucial regulator of vasculogenesis (embryologic blood vessel development from mesodermal elements) and a potent inducer of vascular permeability and angiogenesis (neovascularization). VEGF-C and VEGF-D regulate lymphangiogenesis. VEGF receptors (VEGFR) are tyrosine kinases.
Three VEGFRs have been identified:
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VEGFR-1 has high affinity for VEGF-A, VEGF-B, and PlGF. Functionally, it acts as a negative regulator of VEGF-A signaling by limiting the amount of ligand available to VEGFR-2.
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VEGFR-2 is the primary mediator of the mitogenic, angiogenic, and vascular permeability effects of VEGF-A.
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VEGFR-3 mediates the angiogenic effects of VEGF-C and VEGF-D on lymphatic vessels.
Although VEGF-A and its receptors are most studied in relation to the vascular endothelium, they are also present in other tissues and organ systems, a finding that underscores other possible physiological roles, such as retinal leukostasis and neuroprotection. In addition, VEGF-A may play a role in regulating IOP by elevating levels of nitric oxide (NO), which increases aqueous outflow facility. VEGF-A upregulates expression of endothelial NO synthase (eNOS), which produces NO; VEGF-A blockage may cause IOP elevation by decreasing NO production.
VEGF-A levels in ocular fluids are elevated not only in patients with active ocular neovascularization from proliferative diabetic retinopathy but also after central retinal vein occlusion and in eyes with iris neovascularization. The expression of VEGF is increased by hypoxia in retinal endothelial cells, retinal pericytes, Müller cells, retinal pigment epithelium cells, and the NPE cells of the ciliary body. Also, levels of VEGF-A in the aqueous humor increase in response to anterior segment ischemia in animal models, as well as in response to retinal hypoxia. Aqueous VEGF-A levels fall after intravitreal injection of anti-VEGF agents.
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Karaman S, Leppänen VM, Alitalo K. Vascular endothelial growth factor signaling in development and disease. Development. 2018;145(14):1–8.
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Penn JS, Madan A, Caldwell RB, Bartoli M, Caldwell RW, Hartnett ME. Vascular endothelial growth factor in eye disease. Prog Retin Eye Res. 2008;27(4):331–371.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.