The multifunctional choroid

Abstract

The choroid of the eye is primarily a vascular structure supplying the outer retina. It has several unusual features: It contains large membrane-lined lacunae, which, at least in birds, function as part of the lymphatic drainage of the eye and which can change their volume dramatically, thereby changing the thickness of the choroid as much as four-fold over a few days (much less in primates). It contains non-vascular smooth muscle cells, especially behind the fovea, the contraction of which may thin the choroid, thereby opposing the thickening caused by expansion of the lacunae. It has intrinsic choroidal neurons, also mostly behind the central retina, which may control these muscles and may modulate choroidal blood flow as well. These neurons receive sympathetic, parasympathetic and nitrergic innervation. The choroid has several functions: Its vasculature is the major supply for the outer retina; impairment of the flow of oxygen from choroid to retina may cause Age-Related Macular Degeneration. The choroidal blood flow, which is as great as in any other organ, may also cool and warm the retina. In addition to its vascular functions, the choroid contains secretory cells, probably involved in modulation of vascularization and in growth of the sclera. Finally, the dramatic changes in choroidal thickness move the retina forward and back, bringing the photoreceptors into the plane of focus, a function demonstrated by the thinning of the choroid that occurs when the focal plane is moved back by the wearing of negative lenses, and, conversely, by the thickening that occurs when positive lenses are worn. In addition to focusing the eye, more slowly than accommodation and more quickly than emmetropization, we argue that the choroidal thickness changes also are correlated with changes in the growth of the sclera, and hence of the eye. Because transient increases in choroidal thickness are followed by a prolonged decrease in synthesis of extracellular matrix molecules and a slowing of ocular elongation, and attempts to decouple the choroidal and scleral changes have largely failed, it seems that the thickening of the choroid may be mechanistically linked to the scleral synthesis of macromolecules, and thus may play an important role in the homeostatic control of eye growth, and, consequently, in the etiology of myopia and hyperopia.

Figure 1

Photomicrograph of the three tunics at the back of the primate eye. From: Remington, LA; Clinical Anatomy of the Visual System; 2^nd Edition; 2005. Reproduced with permission © Elsevier.

Figure 2

Histology of the choroid. A. Schematic of the layers of the choroid. Reproduced with permission from Remington, LA. Clinical Anatomy of the Visual System. © Elsevier. B. Semithin resin section of the outer retina and choroid in the primate eye. RPE: retinal pigment epithelium ; CC, choriocapillaris; SL: Sattler's layer; HL: Haller's layer. Reproduced with permission from Forrester et al., 2002. The Eye: Basic Sciences in Practice © Elsevier.

Figure 3

Histology of the choriocapillaris. A. The choriocapillaris is located adjacent to Bruch's membrane. Reproduced with permission from Remington, LA (2005) Clinical Anatomy of the Visual System © Elsevier. B. Each feeder arteriole in Sattler's layer supplies a hexagonally-arrayed area of capillaries. From: Forrester et al., 2002 “The Eye: Basic Sciences in Practice. Reproduced with permissioin © Elsevier.

Figure 4

Light and electron micrographs of the lamina fusca. (a) Light micrograph (retina above, sclera below) showing the lamina fusca, unusually thick in this case, as a dark band at the bottom of the photograph. (b) Electron micrograph (same orientation) showing the stacked, tightly apposed cells making up the lamina fusca. Photographs courtesy of M. Egle De Stefano.

Figure 5

The pterygopalatine ganglion (PPG). A, B. Confocal micrograph of neurons in the PPG labeled for nNOS (green), and for Texas red (DtxR) anterogradely transported from the superior salivatory nucleus-PPG pathway (N VII). Postganglionic nitrergic neurons of the pterygopalatine ganglion were closely associated with anterogradely labeled preganglionic nerve fibers and boutons (yellow color at arrowheads represents sites of closest proximity). Reproduced with permission from Schrödl et al., 2006 © Association for Research in Vision and Ophthalmology. C. Schematic view of the left Harderian gland and associated pterygopalatine plexus from the nasal side. OPH: ophthalmic nerve; receives fibers from the PPG. Rostral is to the right and superior to the top. D. Schematic of the left Harderian gland, from the dorsal aspect. Nerves course to nearby artery; perivascular plexuses form on vessels in the choroid. Reproduced with permission from Cuthbertson et al., 1997 © Wiley.

Figure 6

The intrinsic neurons of the human choroid immunolabeled for nNOS (left) and vasoactive intestinal polypeptide (VIP) (right). Left: Nitric oxide synthase labeling in the cytoplasm of ICNs (arrows) and weak staining in the axons of these neurons (arrowheads). Right: Staining for antibodies against VIP in cytoplasm (arrow) and axon (arrowhead). Approximately 200X magnification. Reproduced with permission from Flugel et al., 1994 © Association for Research in Vision and Ophthalmology.

Figure 7

Non vascular smooth muscle of the primate (A) and chick (B) eyes. A. Suprachoroid and inner sclera contain cells positive for smooth muscle α-actin (blue chromogen counterstained with nuclear fast red). Reproduced with permission from Poukens et al., 1998 © Association for Research in Vision and Ophthalmology. B. Electron micrograph of choroidal cells labeled with antibodies to smooth muscle actin (black dots), showing long fibers not associated with blood vessels. M, muscle cell; F, fibroblast; C, collagen. Reproduced with permission from Wallman et al., 1995 © Association for Research in Vision and Ophthalmology.

Figure 8

Diagram of the lymphatic system of the avian choroid. Veins (V) and arteries (A) traverse the eye wall from the sclera (S) through the suprachoroid and stroma, where they branch into arterioles (a) and venules (v), to the choriocapillaris where they form capillaries (c). Large lymphatic vessels (L) are in the suprachoroid and branch into lymphatic capillaries (l) that reach the choriocapillaris. Reproduced with permission from DeStefano & Mugnaini, 1997 © Association for Research in Vision and Ophthalmology.

Figure 9

Oxygen tension profile through a vascular retina (rat). The measurements are from two sequential penetrations (circles) and withdrawals (triangles) of the electrode. The intraretinal oxygen distribution reflects the relative oxygen sources and sinks within the retina and choroid. Reproduced with permission from Yu and Cringle, 2001 © Elsevier.

Figure 10

Choroidal modulation of refractive state. A. Unfixed hemisected chick eyes. Arrowheads delimit choroidal boundaries. B. Plastic-embedded sections of the back of the eyes. L, lacuna; P, pigment cells; PE, retinal pigment epithelium; arrowhead, choriocapillaris. C, One-mm-thick section of the posterior eye wall. Ch, choroid, delimited by arrows. Reproduced with permission from Wallman et al., 1995 © Elsevier. D. Thickness of the retina+choroid as a function of retinal defocus induced by spectacle lenses. Reproduced with permission from Wildsoet & Wallman, 1995 © Elsevier.

Figure 11

Modulation of choroidal thickness in marmosets (A), guinea pigs (B) and macaques (C). A. Marmosets. Eyes were made hyperopic by lid suture and became myopic after lid opening. Interocular difference (experimental minus control eye) in refractive errors are plotted against interocular differences in choroidal thickness for all eyes. Eyes with more hyperopia had thicker choroids and vice versa. Reproduced with permission from Troilo et al., 2000 © Association for Research in Vision and Ophthalmology. B. Guinea pigs. Mean differences in choroidal thickness between eyes wearing lenses of different magnitude, or plano, and their respective fellow untreated eyes. The mean difference in untreated age-matched controls (AM) are also shown. * p<0.05; *** p<0.001. Reproduced with permission from Howlett & McFadden, 2009 © Elsevier. C. Macaques. Choroidal thickness as a function of refractive error for the right eyes of monkeys treated with binocular, equal-powered, negative (solid symbols) or positive (open symbols) lenses. Reproduced with permission from Hung et al., 2000 © Association for Research in Vision and Ophthalmology.

Figure 12

The diurnal rhythm in the mean thickness of the chick choroid. Arrows denote midnight. Solid curve is the sine wave fit to the data (dotted line and standard error bars). Reproduced with permission from Nickla et al., 1998 © Elsevier.

Figure 13

Incorporation of S-35 into proteoglycans in 6mm punches of posterior sclera in chicks. Left: Choroids from eyes recovering from deprivation myopia and normal eyes. Right: Choroids from eyes wearing positive, negative or plano lenses. Bars are standard errors of the mean. Reproduced with permission from Wallman et al., 1995 © Elsevier.

Figure 14

Interocular difference between lens-wearing eyes and fellow control eyes in chicks. The defocus-induced changes in refractive error are linear from −10 D to +15 D (solid symbols). Open symbols are from untreated birds. From: Irving et al., 1992.

Figure 15

Human eye with the sclera removed from the equator to the posterior pole; the cornea is facing down. Yellow PbO powder was dusted onto the choroid and then the IOP was increased by saline injections. Note that the eye does not balloon, but expands in the antero-posterior direction assuming an ellipsoid shape. Reproduced with permission from Van Alphen, 1985 © Elsevier.

Figure 16

Transient increases in choroidal thickness measured 3 hours after daily brief vision or stroboscopic stimulation, both of which inhibit the development of myopia in response to form deprivation or negative lens wear. Reproduced with permission from Nickla, 2007 © Elsevier.

Figure 17

The effect of choroidal conditioned medium from normal eyes, form-deprived eyes, and recovering eyes, compared to the fellow controls, on glycosaminoglycan synthesis in cartilaginous sclera from normal eyes. Left: sulfate incorporation into scleral glycosaminoglycans. Right: Data converted to ratios between the experimental and control eye conditions. Reproduced with permission from Marzani & Wallman, 1997 © Association for Research in Vision and Ophthalmology.

Figure 18

The effects of visual manipulations on choroidal retinoic acid synthesis. Conditions that increase ocular elongation (form deprivation and negative lens wear) result in significant decreases in choroidal retinoic acid synthesis, whereas conditions that inhibit ocular growth (removing the diffuser, and positive lens wear) result in significant increases in retinoic acid synthesis. Reproduced with permission from Mertz & Wallman, 2000 © Elsevier.

Figure 19

Effects of dopamine agonists on changes in choroidal thickness over 3 hours from the injection into eyes wearing −10 D lenses. Both effective growth inhibitors result in transient increases in choroidal thickness. Unpublished data.

Figure 20

The effects of L-NAME on the choroidal response to myopic defocus measured after 7 hours. The non-specific NOS inhibitior L-NAME inhibits the choroidal thickening in response to myopic defocus caused by prior form deprivation (Recovery) and positive lens wear (Lens). Redrawn from: Nickla & Wildsoet, 2004.

Figure 21

The effects of L-NAME on choroidal thickness (A) and refractive error (B) when given prior to brief daily periods of vision over 4 days, during the development of form deprivation myopia. A. The change in choroidal thickness measured after 2 hours of vision. L-NAME prevented the thickening in response to vision (L-NAME vs saline). B. L-NAME prevented the inhibitory effects of vision on the development of myopia: eyes become significantly more myopic than saline controls. Reproduced with permission from Nickla et al., 2006 © Elsevier.

Figure 22

The effects of several NOS inhibitors on the responses to positive lens-induced myopic defocus on (A) choroidal thickness, (B) refractive error and (C) ocular elongation. A. Change in choroidal thickness measured 7 hours after the injection. Only the inhibitor most specific for nNOS (Nw-PLA) prevented the choroidal thickening response in a dose-dependent manner (bottom panel). B. Refractive error measured 48 hours after the injection. Only Nw-PLA prevented the refractive response to the myopic defocus; eyes became significantly less hyperopic than saline controls. C. Change in axial length measured 24 hours after the injection. Nw-PLA prevented the growth inhibition in response to the myopic defocus; eyes grew significantly longer than saline controls. Fellow: untreated fellow eyes. Nw-PLA, n-omega propyl-L-arginine (nNOS inhibitor); L-NIO, N-(1-iminoethyl)-L-ornithine dihydrochloride (less specific eNOS inhibitor); L-NIL, N-(1-iminoethyl)-L-Lysine hydrochloride (less specific iNOS inhibitor). Reproduced with permission from Nickla et al., 2009 © Elsevier.

Figure 23

Phase differences and growth rates in chicks exposed to myopic and hyperopic defocus induced by spectacle lenses. Mean ocular growth rate (μm/24 hrs) as a function of the mean difference in phase on the preceding day, between the rhythms in axial length and choroidal thickness. The correlation is significant at p<0.05. Reproduced with permission from Nickla, 2006 © Springer.