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Figure 1: Regulation of Blood Flow in the Different addition, the vessels of the retina and the ONH are influenced by the
Parts of the Eye
activity of the neural and glial cells (so-called neurovascular coupling).
VSMC VEC The chorioidal vessels are mainly controlled by the autonomic nerve
system. Due to the blood–retinal barrier, circulating hormones such as
ET-1 or angiontensin II have no direct access to smooth-muscle cells
NO, ET, etc. (SMCs) and pericytes; therefore, they have relatively little effect on
retinal circulation (see Figure 1). The situation is different in the choroid,
which has fenestrated capillaries. Even larger molecules, such as
hormones, escape the vessels and obtain direct access to SMC. These
Autonomic hormones in the choroid can also diffuse, to some extent, into the ONH.
Circulating Hormones and
Neuro-vascular Circulating molecules such as ET, vascular endothelial growth factor
(VEGF) or matrix metalloproteinases (MMPs) can diffuse from the
choroid into the ONH and neighbouring retina and reach the vessels
from the outside. In this way, they are also able to influence the
blood–brain barrier, which in extreme situations is weakened to
The vessels in the different parts of the eye are regulated differently. While they are all
such an extent that even erythrocytes are able to escape from the
controlled by the vascular endothelial cells (VECs), the retinal cells are also controlled
by neural tissue, the choriod by autonomic innervation and the optic nerve head (ONH) by vessels. This leads to the so-called splinter haemorrhages at the
circulating hormones. VSMC = vascular smooth-muscle cells; NO = nitrous oxide;
border of the ONH (see Figure 2).
ET = endothelin. Source: Flammer and Mozaffarieh, 2008.
Figure 2: Optic Disc Haemorrhages in Glaucoma
The Oxygen Paradox
Oxygen is crucial for the survival of tissues, but at the same time it is
also potentially very toxic. Reactive oxidative species (ROS) damage the
cell structures. ROS are mainly produced in the mitochondria. ROS
production depends on the local oxygen tension and on electrical
potential of the mitochondria.
The latter is a proportional function
reduced to oxidised redox carrier in the respiratory chain. If oxygen
supply is more or less constantly reduced (e.g. in cases of
arteriosclerosis or of multiple sclerosis), the tissue can adapt to some
extent. However, if the oxygen supply is low, tissue infarction may result.
A slight and short drop in oxygen supply leads to what is termed ‘pre-
conditioning’. In this way, the tissue can better tolerate subsequent
B decreases in oxygen. If the oxygen decrease is stronger, ROS production
A can exceed the organism’s capacity to cope with free radicals. As a
consequence, oxidative stress damages cellular structures. To some
extent, these cellular structures can still be repaired; however, if the
Even larger molecules such as endothelin (ET) or matrix metalloproteinases (MMPs) can
induced damage exceeds the capacity for repair, structural damage will
diffuse from the fenestrated vessels in the choroid into the optic nerve head and the
remain. After repeated insults, the structural damages build up,
adjacent retina. A weakening of the blood–brain barrier (A) at the level of the endothelial
cells (e.g. by endothelin or by vascular endothelial growth factor) leads to leakage of
ultimately leading to clinically detectable disease.
molecules such as fluorescein (B). If at the same time the basal membrane is weakened, e.g.
by MMP-9, then even erythrocytes can escape, leading to splinter haemorrhages (C).
Source: Grieshaber and Flammer, 2008.
An insufficient oxygen supply to a certain tissue can be due to a
muscles increases dramatically. When we move quickly from a warm to structural damage of the vessels (e.g. an atherosclerosis or
a cold environment, our circulation adapts to redistribute body thrombosis) or due to vascular dysregulation. Such a dysregulation
temperature in order to avoid too much heat loss through the skin and, can be local (e.g. due to a local dysfunction of the endothelial cells) or
as an example, to keep the temperature of the back of the eye constant. may be more or less systemic. The term vascular dysregulation
syndrome in the context of glaucoma was first introduced by
The overall blood flow in the body is regulated by the cardiac output, Flammer.
Later, a distinction was made between primary and
which is mainly controlled by the autonomic nervous system and secondary vascular dysregulation. A systemic vascular dysregulation
circulating hormones. However, the distribution of this cardiac output to can be secondary to another disease, e.g. secondary vascular
different organs or parts of organs is regulated by the relative local dysregulation (SVD) in multiple sclerosis.
However, primary vascular
resistance to flow. dysregulation (PVD) occurs in otherwise healthy subjects. While
subjects with SVD have a reduced baseline OBF, subjects with PVD
Regulation of Local Resistance in the Eye have compromised autoregulation of ocular perfusion. This explains
The vessels of the eye are, similar to all other blood vessels, controlled why SVD is a weak and PVD a strong risk factor for glaucomatous
by the vascular endothelial cells (VECs), which release vasoactive damage. A PVD can often be observed particularly in patients with
molecules. The most important molecule is nitric oxide (NO), which normal-tension glaucoma (NTG). For this reason, PVD will be
induces vasodilation; another is ET-1, which leads to vasoconstriction. In discussed here in some detail.
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