Biochemistry and Physiology of the Cornea
Corneal avascularity is required in order to maintain optical clarity; further, avascularity contributes to the immune privilege of the cornea. Vascular endothelial growth factor A (VEGF-A), which is present in the cornea, is a potent angiogenic agent. Its actions are blocked by a soluble form of VEGF receptor 1 (also known as sflt-1). Suppression of this molecule has been shown to result in increased levels of unbound VEGF-A and in blood vessel growth in the cornea.
Because of the lack of blood vessels in the cornea, oxygen is provided to the cornea via the precorneal tear film, or tear film (which obtains oxygen from the air and eyelid vasculature), and aqueous humor. Glucose is the primary metabolic substrate for the epithelial cells, stromal keratocytes (corneal fibroblasts residing in the stroma), and endothelial cells. The stroma receives glucose primarily from the aqueous humor by carrier-mediated transport through the endothelium; the epithelium receives glucose by passive diffusion through the stroma and from the tear film. The precorneal tear film and limbal vessels supply approximately 10% of the glucose used by the cornea. Glucose is metabolized in the cornea by all 3 metabolic pathways:
In the epithelium and endothelium, the HMP pathway breaks down 35%–65% of the glucose, but the keratocytes of the stroma metabolize very little glucose via this pathway. The keratocytes lack 6-phosphogluconate dehydrogenase, an important enzyme in the HMP pathway. Pyruvic acid, the end product of glycolysis, is converted either to carbon dioxide and water (via the TCA cycle under aerobic conditions) or to lactic acid (under anaerobic conditions).
Production of lactic acid increases in conditions of oxygen deprivation, as in the case of tight-fitting contact lenses with low oxygen permeability. Accumulation of lactic acid in the cornea has detrimental consequences for vision, such as edema (due to an increase in an osmotic solute load) or stromal acidosis, which can change endothelial morphology and function.
Human corneas possess a remarkably high level of aldehyde dehydrogenase and transketolase. Together, these 2 proteins constitute 40%–50% of the soluble proteins in corneal stroma. Similar to enzyme crystallins of the lens, both aldehyde dehydrogenase and transketolase are thought to contribute to the optical properties of the cornea. Both proteins are also thought to protect corneal cells against free radicals and oxidative damage by absorbing ultraviolet B radiation.
The biomechanical properties of the cornea affect its functional responses. An understanding of these properties can help clinicians to better anticipate or understand the cornea’s responses to stress and strain and also aid in diagnosing and treating corneal disease. The following clinically relevant principles have been confirmed:
The paracentral and peripheral cornea are stiffer than the central cornea because of differing orientation and number of collagen fibrils.
The elastic strength of the corneal stroma is greatest anteriorly and decreases posteriorly; thus, laser in situ keratomileusis (LASIK) flap creation and interruption of the anterior stromal lamellae are thought to disproportionately weaken the cornea and contribute to ectasia.
The stiffness of the cornea increases with age, apparently as a result of natu ral collagen crosslinking.
Ambati BK, Nozaki M, Singh N, et al. Corneal avascularity is due to soluble VEGF receptor-1. Nature. 2006;443(7114):993–997.
Hjortdal JO. Regional elastic performance of the human cornea. J Biomech. 1996;29(7): 931–942.
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.