Retinal venous pressure: the role of endothelin

Abstract

The retinal venous pressure (RVP) can be measured non-invasively. While RVP is equal to or slightly above intraocular pressure (IOP) in healthy people, it is often markedly increased in patients with eye or systemic diseases. Beside a mechanical obstruction, the main cause of such an elevation is a local dysregulation of a retinal vein, particularly a constriction induced by endothelin-1 (ET-1). A local increase of ET-1 can result from a high plasma level, as ET-1 can diffuse from the fenestrated capillaries of the choroid into the optic nerve head (ONH), bypassing the blood retinal barrier. A local increase can also result from increased local production either by a sick neighboring artery or retinal tissue. Generally, the main factors increasing ET-1 are inflammations and hypoxia, either locally or in a remote organ. RVP is known to be increased in patients with glaucoma, retinal vein occlusion (RVO), diabetic retinopathy, high mountain disease, and primary vascular dysregulation (PVD). PVD is the major vascular component of Flammer syndrome (FS). An increase of RVP decreases perfusion pressure, which heightens the risk for hypoxia. An increase of RVP also elevates transmural pressure, which in turn heightens the risk for retinal edema. In patients with RVO, a high level of RVP may not only be a consequence but also a potential cause of the occlusion; therefore, it risks causing a vicious circle. Narrow retinal arteries and particularly dilated retinal veins are known risk indicators for future cardiovascular events. As the major cause for such a retinal venous dilatation is an increased RVP, RVP may likely turn out to be an even stronger predictor.

Keywords: Diabetes mellitus; Dilated retinal veins; Endothelin-1 (ET-1); Flammer syndrome (FS); Glaucoma; Ophthalmodynamometry; Predictive, preventive and personalized medicine; Primary vascular dysregulation (PVD); Retinal vein occlusion (RVO); Retinal venous pressure (RVP); Venous constriction.

Fig. 1

Measurement of retinal venous pressure by an ophthalmodynamometer. (Use of the device demonstrated on a co-worker of our team, with written confirmed consent for publication.)

Fig. 2

Schematic representation of the blood vessels in the optic nerve (from [49], with permission). The central retinal vein runs through the SAS; therefore, retinal venous pressure is equal or higher than the pressure in the SAS. Abbreviations: A arachnoid, C choroid, CRA central retinal artery, Col. Br. collateral branches, CRV central retinal vein, D dura, LC lamina cribrosa, ON optic nerve, PCA posterior ciliary artery, PR prelaminar region, R retina, S sclera, SAS subarachnoid space

Fig. 3

Arteriovenous crossing in a human retina (reproduced from [1]). Retinal arteries and veins are very close both in the optic nerve head and at the arteriovenous crossing in the retina. This allows molecular cross talk between arteries and veins in these specific locations. Left: microscopic view of a histologic specimen. Right: schematic representation of the feasibility of a molecular interference. In physiological conditions, the locally produced endothelin-1 has an effect just on the underlying smooth muscle cells. This is different under pathological conditions (see also Fig. 8)

Fig. 4

Venous narrowing rather than compression at the arteriovenous crossings. a, f Fundus photographs of an arteriovenous (AV) crossing, showing crossing phenomena (arrows). b, g Optical coherence tomography (OCT) sections obtained along the retinal veins at crossings. d, i OCT sections obtained at the crossing, perpendicular to the retinal veins. c, e, h, j OCT images with indications of vascular outlines from the upper OCT images. a–e An AV crossing that shows concealment. The retinal vein shows focal narrowing of the lumen at the crossing. However, the vein does not exhibit signs of compression or flattening. The venous lumen is round, even just under the artery. f–j An AV crossing that shows severe tapering. On fundus photographs, the bloodstream seems to be extremely narrow in the area of the crossing site. OCT sections reveal that the actual venous lumen is larger than portrayed by fundus photograph and maintains a round shape. Red lines indicate arterial outlines, and blue lines indicate venous outlines. (Reproduced from [13], with permission)

Fig. 5

Release of endothelin-1 (ET-1). The vascular endothelial cells release the major part of ET-1 abluminally (for local action) and a smaller part intraluminally, influencing the concentration in the circulating blood (from [50], with permission)

Fig. 6

Hypoxia-inducible factor-1 alpha (HIF-1-alpha). If oxygen concentration in a cell is lowered, less HIF-1 alpha is oxidized and degraded. Thus, more HIF-1 alpha can move into the nucleus, where it acts as a transcription factor for vascular endothelial growth factor, endothelin-1, and others (from [50], with permission)

Fig. 7

Influence of endothelin-1 (ET-1) on blood vessels in the optic nerve head and adjacent retina (reproduced from [31]). (A) Circulating ET-1 reaches just the endothelial cells (A1) and has a more or less neutral effect on the size of the vessels. If the blood-brain barrier is disrupted (A2), it reaches the vascular smooth muscle cells directly and induces vasoconstriction. (B) Hypoxic retina produces ET-1, which diffuses also to neighboring vessels. (C) ET-1 diffuses from fenestrated capillaries of the choroid into the optic nerve head and adjacent retina. This can induce a local constriction of the veins and in turn increase retinal venous pressure

Fig. 8

Schematic representation of an arteriovenous crossing in retina in pathological conditions (reproduced from [1]). Left: a diseased artery produces a higher amount of endothelin-1 (ET-1) inducing a venous constriction. Right: local hypoxia further contributes to the ET-1 level and to the constriction of the vein. This can eventually lead to an RVO

Fig. 9

Clinical picture of retinal vein occlusion

Fig. 10

Stimulation of endothelin receptors. Endothelin stimulates the G-coupled endothelin receptors A. This leads to both opening of the calcium channels and liberation of calcium from internal stores (from [51], with permission)

Fig. 11

The role of endothelin and retinal venous pressure in the pathogenesis of retinal vein occlusion (RVO). The scheme indicates the influence of ET-1 on RVP. Increased RVP reduces PP. If this reduction is not compensated enough by arterial vasodilation, hypoxia will result, inducing possibly a vicious circle that potentially ends in the clinical picture of an RVO. Abbreviations: ET-1 endothelin-1, RVP retinal venous pressure, PP perfusion pressure, BRB blood-retina barrier

Fig. 12

Retinal venous pressure (RVP) in patients with and without diabetic retinopathy (DR). RVP is increased in patients with DR but not in diabetes patients without DR. RVP (mmHg) is plotted with the age (years). Straight lines indicate regression slopes. The black circle indicates the control group, the red triangle represents the group diabetes patients without DR, and the green cross represents patients with DR (reproduced from [35])

Fig. 13

The influence of Flammer syndrome (FS) on retinal venous pressure (RVP). Healthy subjects with FS have slightly higher RVP than healthy subjects without FS. In glaucoma patients, this difference was even larger; the difference between IOP and RVP was greatest in subjects suffering from both glaucoma and FS. Abbreviations: IOP intraocular pressure, RVP retinal venous pressure, POAG/FS+ patients with glaucoma and FS, POAG/FS- patients with glaucoma and without FS, Healthy/FS+ healthy subjects with FS, Healthy/FS- healthy subjects without FS (reproduced from [38])

Fig. 14

Occlusion of a cilioretinal artery (CLRAO) (from [45], with permission). Left: fundus with white ischemic retina with a “cherry-red spot” appearance at the macula in an area supplied by a cilioretinal artery. Right: corresponding fluorescein angiogram

Fig. 15

Changes of the diameter of the retinal veins over time. The temporal dynamic of the size of the veins is illustrated in a patient with Takayasu arteritis. Left: during acute inflammation (of the aorta), the optic nerve head (ONH) of this young patient was pale, and the retinal veins at the border of the ONH were markedly constricted. Right: after treatment of the inflammation, the ONH colored again, and the veins reached nearly normal sizes. Arrows indicate one of these veins