Diabetic retinopathy is a clinically well-defined, sight-threatening, chronic microvascular
complication that eventually affects virtually all patients with diabetes. Diabetic
retinopathy is characterized by gradually progressive alterations in the retinal microvasculature,
leading to areas of retinal nonperfusion, increased vasopermeability, and in response
to retinal nonperfusion, pathologic intraocular proliferation of retinal vessels (1
–3).
Most diabetes researchers and clinicians are aware of the major advances made in understanding
the pathobiology of proliferative diabetic retinopathy. However mechanisms underlying
the progressive alterations in retinal microvessels, which precede and stimulate neovascularization,
are less well-known. In this review, current information about the pathogenesis of
the primary lesion of diabetic retinopathy, retinal capillary vasoregression (see
Fig. 1), is presented.
FIG. 1.
Phenotype of vasoregression in the diabetic retina. In both experimental diabetic
rats and diabetic humans, capillary occlusions occur. Nondiabetic (A) and 6-month
diabetic rat retina with acellular capillaries (arrows) (B). Nondiabetic (C) and diabetic
(D) human retinal digest preparation. Periodic acid-Schiff staining (original magnification
×250).
Diabetic retinopathy is often considered as a complication that contrasts with other
vascular sequelae of this disease because it is associated with new vessel formation,
while diabetic heart disease and diabetic nephropathy are characterized by impaired
angiogenesis (4). Diabetic retinopathy is generally grouped with tumor angiogenesis
and is presented as a paradigm of a neovascular disease (5). As outlined in this review,
the natural history of diabetic retinopathy starts with vasoregression. Recent investigations
have brought new insight regarding the primary vasoregressive process that stimulates
angiogenesis, provoking new directions of thinking about possible prevention and intervention
(1).
Diabetic retinopathy starts with the loss of the two cellular components of retinal
capillaries: the pericyte, a vessel support cell, and the endothelial cell. The exact
sequence of loss in humans is not established because early human retinal samples
are not available, but animal studies have provided evidence that pericytes disappear
before endothelial cells start to vanish, leaving acellular capillaries with no blood
flow (6). In response to progressive retinal capillary dropout, the ischemic retina
mounts an angiogenic response from the surrounding capillaries leading to proliferative
diabetic retinopathy. Correlative studies of fluorescein angiography and postmortem
retinal digests in humans show that microaneurysms appear to cluster around areas
of acellular capillaries linking structural damage in situ to clinical markers of
disease progression and suggesting that microaneurysms represent abortive attempts
at neovascularization (7,8).
The mechanism of physiological (sprouting) angiogenesis.
Novel concepts have recently been proposed for physiological angiogenesis also reflecting
mechanisms that might be involved in pathological angiogenesis (9,10). There are some
important molecular players of interest that dominate both developmental and pathologic
retinal angiogenesis. Under physiological conditions, subsets of endothelial cells
in sprouting vessels qualify for different functions (Fig. 2). The tip cells guide
the vessel along a gradient of heparin-bound VEGF (vascular endothelial growth factor)-A
(164) sensed by VEGF receptor-2 expressed on cell extrusions (filopodia) (11). Tip
cells are incapable of proliferation. In contrast, stalk cells do proliferate. These
specialized endothelial cells are prevented from becoming tip cells by lateral inhibition
through the Notch-Dll system, while their proliferative activity is determined by
the availability of VEGF and other growth factors such as angiopoietin (Ang)-2 (12).
The transition from a proliferating to a mature quiescent endothelial cell, i.e.,
the transition from a stalk cell to a so-called phalanx cell, is determined by the
expression of Ang-1 and the firm coverage by pericytes, which render these cells resistant
to growth factor depletion by mechanisms that are poorly understood. On retinal endothelial
cells, Tie-2 receptor activation through Ang-1 binding combines several recruiting
signals for smooth muscle cells (and probably pericytes), including hepatocyte- and
heparin-binding epidermal-like growth factor, but the firm intramural positioning
of pericytes has yet to be explained. As a novel finding, Notch3 is specifically involved
in pericyte recruitment and survival (13).
FIG. 2.
Concept of physiological angiogenesis. 1) In tip cells, VEGF stimulates DLL4/NOTCH
signaling via VEGF-R2, thereby inhibiting tip cell formation and inducing VEGF-R1
expression in the endothelial cells downstream. Astrocyte-derived SDF-1 acts as an
additional chemoattractant, activating CXCR4 in tip cells. 2) In stalk cells, predominance
of VEGF-R1 and activation of Tie-2 by Ang-2 secreted from the tip cell lead to proliferation
and survival. 3) Platelet-derived growth factor receptor (PDGFR)-β+–pericytes are
attracted to the growing sprout by PDGF-B, released from tip cells. Interaction of
recruited pericytes with endothelial cell–derived Jagged-1 induces the expression
of Notch3 and activation of an autoregulatory loop that further enhances Notch3 activation,
thereby promoting pericyte survival, investment, vascular branching, and induction
of smooth muscle cell (SMC) genes. 4) Transforming growth factor (TGF)-β produced
in endothelial cells further induces SMC differentiation and pericytes-derived Ang-1
binds to and activates the Tie-2 receptor on endothelial cells, thereby stimulating
vessel maturation and stabilization.
VEGF and the retina.
Previous work using transgenic mice with isoform-specific expression of VEGF has indicated
that the VEGF-A isoform 164 is the major one required for proper three-dimensional
network formation in the retina (14). One important contributing factor is the balance
between VEGF's diffusibility and its heparin-binding properties. The sole presence
of the diffusible VEGF120 isoform causes severe changes in vessel outgrowth and patterning,
pericyte recruitment, and vessel permeability during early vessel development in the
retina. In contrast, the isolated presence of strongly matrix-associated VEGF188 impairs
arterio-venous differentiation, capillary patterning, and peripheral vascular outgrowth
(15). Another important issue is the relative abundance of growth factors involved
in the development and maturation of the retinal vasculature. In the nondiabetic rodent
retina, VEGF-A (164) is by far the most abundant factor expressed, e.g., exceeding
that of tumor necrosis factor-α by 30,000-fold. The importance of VEGF-A for proper
retinal vascular development is further supported by data from mice with conditional
inactivation of VEGF-A in neuronal tissue. Mouse retinae with a depletion of VEGF
in nestin-expressing cells are characterized by a sparse capillary network, a smaller
capillary width, 25% fewer endothelial cells, and a sixfold increase in capillaries
devoid of both endothelial cells and pericytes, indicating that VEGF is not only an
important developmental growth factor, but also an important survival factor (16).
When these mice are subjected to the mouse model of retinopathy of prematurity, there
is a 94% reduction in new vessel formation.
In patients with active proliferative diabetic retinopathy, VEGF levels are increased,
while in those eyes in which proliferative retinopathy is quiescent, VEGF levels are
either normal or only modestly increased (17). Together these data suggest that VEGF
is the most prominent member of a group of factors that control and facilitate physiological
and pathological angiogenesis.
From a clinical standpoint, the question arises whether there are certain genetic
changes that are associated with the promotion or the inhibition of retinopathy. In
contrast to many other vascular diseases, diabetic retinopathy in general has not
been found to be strongly and unequivocally linked to genetic defects or polymorphisms.
Among the few significantly associated genes are aldose reductase, the receptor for
advanced glycation end products (RAGE), the integrin α2β1, and VEGF. From the Diabetes
Control and Complications Trial (DCCT), it is known that 25% of the risk for retinopathy
development can be explained by genetic factors, which are determined by familial
clustering (18). Al-Kateb et al. (19) analyzed the 16 single nucleotide polymorphisms
of VEGF in type 1 diabetic patients of the DCCT/Epidemiology of Diabetes Interventions
and Complications (EDIC) cohort and tested the association of these polymorphisms
with retinal outcomes after 10 years during the EDIC study. There was a strong association
of VEGF polymorphisms with the development of severe retinopathy but not with retinopathy
progression or diabetic macular edema. Although the familial clustering suggests a
genetic contribution to the risk of developing advanced lesions, the identity and
function of such contributors are completely unknown. Apart from genetic factors,
epigenetic modifications induced by hyperglycemia-induced biochemical changes in the
transcriptional machinery of target cells may play a role that needs to be assessed.
Context-dependent function of the Ang-Tie system.
The Ang-Tie system has received particular attention as a key regulator of adult vascular
homeostasis (20
–23). The receptor tyrosine kinase Tie-2 is expressed on endothelial cells, regulating
vascular remodeling and maturation. The balance between the two ligands Ang-1 and
-2 determines the phosphorylation status of Tie-2, thereby regulating endothelial
barrier function, vessel branching, inflammatory responses, and angiogenesis (24
–26). Ang-1 is considered to be an activator of Tie-2, while Ang-2 is a homologous
ligand that antagonizes Ang-1 activity on Tie-2, acting as an endogenous dominant
negative ligand for Ang-1. During developmental angiogenesis, Ang-1 expression appears
to be the initial step of vessel maturation, causing endothelial cell differentiation
and recruitment of pericyte precursors, which stabilize the new vessels (22,27). Transforming
growth factor-β1 further contributes to the final maturation steps by downregulation
of cell migration and promotion of cell differentiation. Adult vessel remodeling involves
the interplay between VEGF and the ratio of Ang-1 and -2. When the ratio of Ang-2
to Ang-1 is high and VEGF is high in hypoxic tissues, the consequence is sprouting
angiogenesis. In contrast, in the absence of VEGF, Ang-2 upregulation leads to vasoregression.
Isolated downregulation or the absence of Ang-1 causes vessel destabilization through
effects on pericytes (27).
Hyperglycemia and the molecular changes in the early diabetic retina.
The most relevant morphological lesion in the diabetic retina is the acellular, nonperfused
capillary segment (1). It reflects the net result of multiple damaging mechanisms
involving endothelial, matrix, pericyte, and microenvironmental components. Thus retinopathy
does not deviate from all the other vascular phenotypes in diabetes as is often thought.
Diabetic retinopathy is part of a systemic vascular disease in which vasoregression
is the primary evolutionary process. Vasoregression in the diabetic retina starts
with pericyte loss. This is a long-known feature, and it has been consistently reported
in diabetic animals and humans (2,6). As noted above and elaborated upon in a recent
review by Betsholtz and colleagues (28), ligand-receptor systems involved in endothelial-pericyte
(mural) cell signaling determine the fate of pericytes not only during vascular development,
but also during incipient diabetic retinopathy (18). The concept, proposed by Hanahan,
is that Ang-2 overexpression in cooperation with VEGF overexpression leads to pericyte
loss and angiogenesis, while Ang-2 overexpression in the absence of VEGF leads to
vasoregression (25). Figure 3 summarizes the context-dependent expression and regulation
of the Ang-Tie system with the focus on diabetic vasoregression and angiogenesis.
When determined in an experimental diabetic rat model in which pericyte dropout was
precisely ascertained, Ang-2 upregulation (37-fold) preceded the onset of pericyte
dropout (6). In young nondiabetic rats, pericyte dropout was inducible by intravitreal
injection of recombinant Ang-2. Moreover in heterozygous diabetic Ang-2 knockout mice,
pericyte dropout was prevented, and in mice with constitutive retinal overexpression
of Ang-2, pericyte dropout was exaggerated. Together these data suggest that Ang-2
is involved in the pathogenesis of diabetic pericyte loss. Ang-2 upregulation by hypoxia
is an established fact. However the early diabetic (rodent) retina is not hypoxic.
Therefore hyperglycemia-induced regulation of Ang-2 was investigated. Hyperglycemia-induced
mitochondrial overproduction of reactive oxygen species has been shown to induce altered
gene transcription by covalent modification of coregulatory proteins. In renal endothelial
cells, it was found that a complex consisting of the transcriptional co-repressor
mSin3A and the transcription factor Sp3 suppresses transcriptional activity by binding
to a glucose-sensitive GC box in the Ang-2 promoter. Hyperglycemia-induced formation
of methylglyoxal modifies mSin3A resulting in increased recruitment of O-GlcNAc transferase
to an mSin3A-Sp3 complex and a subsequent increased modification of Sp3 by O-linked
N-acetylglucosamine. Gluc-NAc modification of Sp3 causes decreased binding of the
repressor complex to the glucose-responsive GC box in the Ang-2 promoter resulting
in increased Ang-2 expression (27) (Fig. 4).
FIG. 3.
In the mature vasculature, pericyte-derived Ang-1 dominates Ang-2, leading to Tie-2
phosphorylation in endothelial cells. Activation of Tie-2 controls endothelial cell
proliferation and induces intercellular contacts and junctions, thereby stabilizing
retinal vasculature and promoting the formation of the blood-retinal barrier (A).
Diabetes-induced vasoregression is a result of Ang-2 upregulation in the absence of
hypoxia. Retinal endothelial cells and glial cells (Müller cells) express Ang-2 as
a dominant negative ligand blocking Tie-2 phosphorylation. Upregulation of Ang-2 induces
vascular cell depletion and progressive capillary occlusion (B). Growing areas of
nonperfusion lead to upregulation of hypoxia-induced factors such as VEGF and Ang-2.
In pericytes, Notch3 activation under hypoxic conditions induces Ang-2 expression.
Abundance of VEGF without a succinct gradient and elevated Ang-2 levels destabilize
vessels, cause endothelial cell proliferation and pericyte activation. Bone marrow–derived
progenitor cells contribute to pathological angiogenesis (C). P, phosphate. (A high-quality
color representation of this figure is available in the online issue.)
FIG. 4.
Mechanism of hyperglycemia-induced Ang-2 regulation. A: Under physiological (normoglycemic)
conditions, a transcriptional complex (involving the transcriptional corepressor mSin3A)
represses Ang-2 transcription by binding to a glucose-sensitive GC box. B: Transcriptional
activation of Ang-2 through methylglyoxal (AGE)-induced and hexosamine-propagated
modification of SP-3 binding in favor of SP-1 binding. GAPDH, glyceraldehyde-3-phosphate
dehydrogenase; UDP, uridine-5-diphosphate. (A high-quality color representation of
this figure is available in the online issue.)
Pericyte migration: a novel mechanism of diabetic pericyte loss.
Data from human and animal studies have suggested that diabetic pericyte loss is the
result of apoptosis induced by activation of nuclear factor-κB (NF-κB) or, as has
been recently pointed out, by activation of the protein tyrosine phosphatase SHP-1
in an NF-κB independent pathway. Apoptosis is determined by a transient indicator
(e.g., nuclear fragmentation). Still, the number of lost pericytes from apoptotic
pericytes observed in retinal digest specimens is lower than the projected number
of pericytes lost in total after several months of diabetes, suggesting that additional
mechanisms may be involved (29,30). Moreover, the developmental origin and the morphological
diversity of pericytes in retinal capillaries suggest that not all pericytes are alike.
Pfister et al. (31) used quantitative retinal morphology and normal and diabetic mice
with different levels of Ang-2 expression to study which pericytes were lost in the
diabetic retina and whether it was due to changes in Ang-2. The investigators categorized
pericytes into three classes: 1) located at vessel branches (saddle pericytes), 2)
located on straight parts of capillaries, and 3) showing different degrees of detachment
from adjacent endothelial cells (migrating pericytes) (Fig. 5). The investigators
found that saddle pericytes remained unaffected by diabetes while only pericytes on
straight parts of capillaries were reduced in diabetic retinae in parallel with an
increased number of migrating pericytes. In nondiabetic Ang-2–overexpressing animals,
this number was increased by 78%, while in Ang-2–deficient mice, the numbers of migrating
pericytes was reduced by 36% (31). Together, these data favor pericyte migration as
an important mechanism for diabetic pericyte loss.
FIG. 5.
Schematic illustration linking hyperglycemia-induced reactive oxygen species (ROS)
overproduction with Ang-2–dependent vasoregression and combined ischemia/hypoxia-induced
angiogenesis. In healthy retinal capillaries, proper pericyte coverage ensures endothelial
cell survival and integrity of blood-retinal barrier by Ang-1/Tie-2 signaling. Chronic
hyperglycemia induces cell damage and upregulation of Ang-2 in retinal endothelial
cells and Müller cells (MC), leading to retinal pericyte detachment, migration, apoptosis,
and progressive vasoregression. Occluded remnants of capillaries are no longer perfused,
leading to the upregulation of survival/growth factors such as VEGF. During the later
stages, which is not represented in rodent models, increased expression of hypoxia-induced
VEGF and increased Ang-2 levels lead to preretinal neovascularization. HXP, hexosamine
pathway; EC, endothelial cell. (A high-quality color representation of this figure
is available in the online issue.)
The fate of migrating pericytes in the diabetic retina remains uncertain, but inferential
evidence from work on brain pericytes suggests that they migrate away from an injured
capillary for survival (32). As noted in the traumatic brain injury model, stress-induced
migration of pericytes resulted in their survival. Pericytes that stayed at their
vessel location and did not migrate were prone to apoptosis, suggesting that migration
of pericytes away from the capillary enables the pericyte to respond to trophic signaling
molecules in the perivascular compartment. The subsequent functional adaptations may
include differentiation along multiple lineages reflecting the pluripotency of this
enigmatic cell population (33).
After regional hypoxia occurs in the diabetic retina as a result of vasoregression
and capillary dropout, retinal neovascularization occurs in an attempt to restore
oxygen delivery. Both VEGF and Ang-2 are normally induced by hypoxia and cooperate
to induce angiogenesis (34,35). Feng et al. (36), using homozygous Ang-2–deficient
mice, reported spontaneous proliferative retinopathy occurring in room air that mimicked
human retinopathy of prematurity (ROP) in mice. Arteriolar patterning and the formation
of the primary (superficial) and secondary (deep) capillary network were impaired
due to the lack of Ang-2. Over time, the relative increase of VEGF in this model declined,
rendering persistent preretinal proliferations less leaky. Reduced matrix metalloproteinase
(MMP) activity, which is evident in heterozygous Ang-2–deficient mice causing a reduction
in proliferative retinopathy, may be overcome by VEGF-induced MMP regulation in the
complete absence of Ang-2. Thus, Ang-2 appears negligible for retinal neovascularization,
but it is essential for proper vessel development, in particular of the arteriolar
site, and the capillaries in the depth of the retina where diabetic retinopathy starts.
Erythropoietin in the diabetic retina.
Erythropoietin (Epo) is another ischemia-induced growth factor that was recently identified
as being important in the pathogenesis of proliferative diabetic retinopathy. Work
by Takagi and colleagues (37) demonstrated that Epo is increased in eyes with proliferative
diabetic retinopathy, and the experimental inhibition of Epo is as effective as that
of VEGF in the ROP model. More recently, a large consortium (38) reported that promoter
polymorphisms of the Epo gene are associated with proliferative diabetic retinopathy
in patients, with increased promoter activity giving rise to increased Epo transcription.
Critically, the effect of exogenous Epo depends on the temporal relation to the induction
of vasoregression (39). In the ROP model, Epo administered prior to the induction
of vasoregression (i.e., before mice went into the hyperoxic chamber) reduced vasoregression
and, consequently, responsive neovascularization, while Epo, administered after vasoregression
had occurred, induced increased neovascularization. The effect of Epo is mediated
by a complex consisting of the Epo receptor, which is expressed throughout the entire
retina, and the common chain receptor, which is expressed only in the vicinity of
the superficial vascular layer, i.e., in the layer in which most neovascularizations
develop. Low-dose Epo, which does not induce erythropoiesis over a period of up to
6 months, inhibited oxidative stress in the retinae of STZ-diabetic rats and reduced
VEGF and Ang-2 levels (40). The formation of acellular capillaries and the loss of
pericytes were also reduced in these Epo-treated diabetic animals. The formation of
acellular capillaries and the loss of pericytes were reduced in treated diabetic animals.
Of particular note, the increased level of leukostasis (i.e., local capillary obstruction
by leukocytes [see below]) remained unaffected by Epo treatment (Q. Wang et al., unpublished
data), suggesting that leukostasis does not play a major role in causing vasoregression
in the diabetic retina.
Factors modulating vasoregression
Inflammation.
Inflammation is an important pathogenetic aspect of diabetic retinopathy based on
the findings that inflammatory cytokines and mediators are upregulated in the diabetic
retina, and that leukostasis occurs because of adhesion molecule upregulation (41
–45). As a novel aspect, microglial cells transdifferentiating from bone marow–derived
cells may contribute to the propagation of inflammatory vessel damage. This area has
been the subject of two recent exciting reviews (46,47) addressing the multifaceted
and important link between inflammation and diabetic retinal vasoregression.
Leukostasis.
Since the early reports by Schmidt-Schönbein, leukostasis has evolved as a mechanism
by which activated bone marrow–derived cells may damage retinal capillary endothelial
cells (44,48). It was noted that leukocytes adhered to the diabetic endothelium in
all vascular beds of the retina, and some leukocytes obstruct capillaries. Several
studies implied that correction of leukostasis necessarily preserved retinal capillaries
from occlusion (49
–51). However, as outlined above, new experimental evidence suggests that the prevention
of acellular capillaries succeeds without correction of leukostasis (42,52) (Q. Wang
et al., unpublished data).
Endothelial progenitor cells.
Another bone marrow–derived cell population that is able to interact with the endothelium
in damaged tissues is the endothelial progenitor cell (EPC). However, in contrast
to leukocytes, EPCs have attracted much interest because of their potential role in
vascular repair. From studies using models of proliferative retinopathy, the contribution
of hematopoietic stem cells to retinal neovascularization has been proposed (53).
In this context, the chemokine SDF-1 was established as an important promoter of adult
retinal angiogenesis in a model of laser-induced retinal vein occlusion (54). Blocking
SDF-1 activity abolished the recruitment of hematopoietic stem cell–derived endothelial
precursors and local endothelial cell–driven ischemic repair, preventing preretinal
neovascularization.
The question of whether EPCs can support the repair of damaged endothelial cells was
also addressed in experimental studies. Using rodent models in which capillary endothelial
cells were damaged by different mechanisms, Caballero et al. (55) used labeled CD34+
cells from both nondiabetic and diabetic origin and found that only nondiabetic cells
were able to integrate into the damaged vasculature. EPCs, which have impaired function,
may be restored by improvements in mobilization, e.g., by statins, or by drugs that
improve function, adding to the self-repair of damaged capillaries in the diabetic
retina.
Apart from being expressed on endothelial cells, Tie-2 is expressed on bone marrow–derived
monocytes/macrophages (TEM), and the interaction with local tissue Ang-2 (such as
in hypoxic tumor areas) promotes angiogenesis (56). High Ang-2 in the diabetic retina
may cause a recruiting signal for TEM and direct them to the retina. The relevance
of this pathway and the possible role in vasoregression await clarification.
Lipids and fatty acids.
Vasoregression in the diabetic retina may also result from hyperglycemia-induced modifications
of the levels or the chemical make-up of lipids and fatty acid–based lipid mediators,
as suggested by clinical and experimental studies such as the DCCT and others (57
–59). Two distinct entities of modifications have been proposed: 1) posttranslational
modification of lipoproteins and 2) diabetes-induced alterations in the biosynthesis
of eicosanoids. Examples for modified lipoproteins as possible mediators of retinal
vessel toxicity have been given by Lyons and colleagues (60). They showed that oxidized
LDL is toxic for pericyte and can contribute to pericyte death. Diabetes-induced changes
in proinflammatory eicosanoids are derived from arachidonic acid, and anti-inflammatory
resolvins and protectins are derived from ω-3 polyunsaturated fatty acids. In the
diabetic retina, elongase and desaturase profiles are substantially altered leading
to a decrease in these ω-3 unsaturated fatty acids (61). As they can affect retinal
gene expression with subsequent changes in cell differentiation and survival, diabetes-induced
reductions in ω-3 PUFAs and increases in arachidonic acid can contribute to both vasoregression
and neovascularization because of the lack in antiproliferative and proinflammatory
effects. In addition to their proinflammatory effects, eicosanoids can increase Ang-2
expression either directly or via the modification of VEGF expression (62).
Conclusion.
The sight-threatening proliferative diabetic retinopathy familiar to clinical diabetologists
is not the primary pathogenic response of the retina to chronic hyperglycemia. Rather,
it is an attempted compensation for retinal hypoxia caused by loss of capillary pericytes
and followed by formation of acellular, nonperfused capillaries. This vasoregression
is the primary pathogenic response of the retina to chronic hyperglycemia. Central
mediators of pericyte loss and acellular capillary formation include hyperglycemia-induced
alterations in levels of VEGF isoforms, Ang-1 and -2; recruitment of activated macrophages,
microglia, and/or leukocytes from the bone marrow; increased proinflammatory eicosanoid
production; and decreased anti-inflammatory resolvins and protectins derived from
ω-3 polyunsaturated fatty acids. Many of these changes are mediated by consequences
of hyperglycemia-induced reactive oxygen species. Further elucidation of the mechanisms
by which chronic hyperglycemia causes intraretinal vasoregression (Fig. 6) will provide
new targets for pharmaceutical intervention before irreversible retinal ischemia and
secondary proliferative retinopathy necessitate damaging treatments such as panretinal
laser photocoagulation.
FIG. 6.
Summary illustration of mechanisms by which chronic hyperglycemia causes intraretinal
vasoregression. EC, endothelial cell; EPC, endothelial progenitor cells; mtROS, mitochondrial
reactive oxygen species; PC, pericytes.