Ординатура / Офтальмология / Учебные материалы / Retinal Vascular Disease Joussen Springer
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Fig. 2.3. Visualization of the natural regression of the hyaloid vasculature using live imaging in mice. a Live, in vivo imaging can be used to visualize the various ocular vascular plexuses including the iris vasculature at the front of the eye (red), the hyaloidal vessels in the vitreal cavity (blue), and the retinal vessels at the back of the eye (green) (adapted from [36]). b Using in vivo imaging, natural regression of the hyaloidal vasculature can be followed demonstrating the existence of a full hyaloidal network in 1-week-old mice (left), a regressing hyaloidal vasculature in 16-day-old mice (middle), and a nearly fully regressed hyaloidal vasculature in 22-day-old mice (right)
The superficial vascular plexus within the ganglion cell layer is the first to form, with the early stages of development beginning at gestational age 14 to 16 weeks in humans [17, 34]. This plexus grows radially from the optic nerve head toward the retinal periphery (Fig. 2.4A). Currently there is conflicting evidence as to whether the superficial plexus forms by the process of vasculogenesis or angiogenesis. While there is no evidence of angioblasts ahead of the migrating vascular front in rodent species [16, 17], results from the few studies investigating human retinal development suggest that vasculogenesis may be involved [7].
2.5.1 The Role of Astrocytes
Astrocytic neuroglia play a critical role during retinal vascular development. Only species with vascularized retinas are known to express retinal astrocytes, and within the retinas of those species, astrocytes are only observed in regions where vascularization occurs. For example, astrocytes do not develop in the macula, which also remains avascular. Astrocytes emerge from the optic nerve head prior to neovascularization. As the retina becomes hypoxic, the retinal glial cells, consisting of astrocytes within the ganglion cell layer and Müller cells whose processes extend throughout the neural retina, respond to hypoxia by
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Fig. 2.4. Normal development of the mouse retinal vasculature. a The superficial plexus forms after birth in mice as vessels emerge from the optic nerve head and migrate out toward the retinal periphery during the first 10 days. By 3 weeks after birth, a normal adult-like vasculature has formed. b During development of the mouse retinal vasculature, three vascular plexuses are formed. During the 1st week after birth the superficial plexus forms within the ganglion cell layer (GCL), the intermediate plexus forms at the inner edge of the inner nuclear layer (INL) by the 2nd week after birth, and the deep plexus forms at the outer edge of the INL by the 3rd week. This vascular development is similar to the formation of the human retinal vasculature during the 3rd trimester in utero. (Images adapted from [11])
secreting growth factors, thus initiating proliferation of endothelial cells and vascularization of the retina [40]. Vascular endothelial growth factor (VEGF) plays an important role during retinal vascular development. Astrocytes secrete VEGF, which the endothelial cells respond to through VEGF receptors on the endothelial cell surface. Other growth factors such as insu- lin-like growth factor-1 (IGF-1) and fibroblast growth factors (FGFs) are also likely to participate in the initiation of retinal vascular development.
In addition to their important roles as initiators of retinal vascular development, astrocytes also play a critical role during guidance and maintenance of the neovascular plexus. During formation of the superficial plexus, retinal vessels are intimately associated with astrocytes [37, 40]. These neovessels develop in
direct contact with the astrocytes, migrating along the preexisting astrocytic template (Fig. 2.5). Recent evidence has demonstrated that VEGF165 [39] and R- cadherin mediated cell-cell adhesion [11] are critical for normal astrocytic guidance of the superficial vessels. There are three main VEGF-A isoforms,
VEGF122, VEGF165, and VEGF188, each named for protein size. VEGF165 and VEGF188 both have heparin-
sulfate binding motifs that are eliminated in the VEGF122 splice variant. This limits the permeability of VEGF165 and VEGF188, causing these molecules to remain in the extracellular milieu proximate to the cells from which they were expressed. Thus, as VEGF165 is secreted by the astrocytes in response to retinal hypoxia, the limited diffusion properties result in a VEGF pattern similar to the underlying
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Fig. 2.5. Retinal vessels develop in close association with retinal astrocytes. a Retinal astrocytes (GFAP, green) emerge from the optic nerve head ahead of the retinal vessels (red), which subsequently grow along the preexisting astrocytic template (b). Mature retinal vessels (red) are wrapped by astrocytes (green) helping to form the blood-retinal barrier (blue stains the underlying nerve fiber layer). (Images adapted from [11])
astrocytes. Subsequent interactions between VEGF and the endothelial-VEGF receptors lead to the initial endothelial cell-astrocyte association.
Continuous interactions between endothelial cells and the underlying astrocytic template are mediated by adherens junctions. R-cadherin molecules on the astrocyte cell surface directly interact with adherence molecules on the endothelial cells (presumably other cadherin molecules), mediating the lasting endothelial cell-astrocyte association. When R-cad- herin function is blocked, endothelial cells are no longer able to migrate along the astrocytic template and the superficial vasculature fails to develop normally [11]. Thus, through specific expression of growth factors and adhesion molecules, the astrocytes form a template that guides vascular development and patterning in the retina. As the vasculature matures, astrocytes begin to wrap around the newly formed vessels and this vessel-astrocyte association remains as an important aspect of the blood-retinal barrier throughout the adult life (Fig. 2.5).
2.5.2The Role of Subcellular Endothelial Processes
Endothelial cells must be able to respond specifically to guidance cues expressed by the astrocytic template. This is mediated by growth factor receptors and specific adhesion molecules expressed at the endothelial cell surface. However, since VEGF165 has limited diffusion capabilities and subsequent adherence junctions are between membrane-bound molecules, the endothelial cells must have a method of accessing these molecular guidance cues. To this extent, specialized endothelial cells at the tips of the migrating vascular front extend long filopodial-like processes that can access and initially respond to environmental cues (Fig. 2.6) [11, 18]. These processes mediate response to conditions within the regions ahead of the migrating vascular front, and thus mediate response to the astrocytic-guidance cues. Although not directly proven, evidence strongly suggests that the filopodia that fall along underlying astrocytes are stabilized by interactions between VEGF and its receptor, as well as the formation of R-
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Fig. 2.6. Filopodial processes are extended from the tips of retinal endothelial cells at the developing vascular front.
Isolectin Griffonia simplicifolia staining of the developing retinal vasculature allows visualization of the filopodial processes. (Images adapted from [11])
cadherin mediated adherence junctions. Longer, more established filopodial extensions tend to colocalize with underlying astrocytes [11, 18]. These stabilized filopodia then remain, initiating vascular growth and migration in that direction, while other non-stabilized filopodia are retracted. In this manner, the endothelial cells are guided along the astrocytic template during retinal development.
2.6Development of the Deep Retinal Vascular Plexuses
As the retina continues to expand due to the final development and differentiation of neurons within the inner nuclear layer, the superficial vessels will eventually branch and begin formation of the deep and intermediate vascular plexuses. These vascular branches sprout perpendicular to the superficial plexus and dive toward the outer edge of the inner nuclear layer where they anastomose laterally and form a planar microvascular plexus. Eventually a third, intermediate vascular plexus will form at the inner edge of the inner nuclear layer from sprouts off the branches between the superficial and deep plexus (Fig. 2.4). While debate continues as to whether the superficial plexus forms by vasculogenesis or angiogenesis, general consensus is that the deep and intermediate plexuses fom solely by the process of angiogenesis.
The general principles that mediate formation of the deep vascular plexuses are similar to those that initiate and guide formation of the superficial plexus. A cytokine gradient is created toward the outer retina, mainly through the expression of growth facrs by retinal pigment epithelium (RPE), photoreceptors and Müller cells in response to the growing hypoxia created by neuronal growth, differentiation, and activity. This gradient is sensed by endothelial cells
in the superficial plexus initiating new growth toward the deep plexus [10]. Filopodia-like sprouts are again observed extended ahead of vessels migrating toward the deep plexus, suggesting that these endothelial cells can also respond to specific environmental guidance cues (Fig. 2.7). Indeed, R-cadhe- rin expression is also present in the zones where the deep and intermediate plexus forms, just prior to, and throughout neovascularization of these regions. In mouse models, if R-cadherin mediated adhesion is blocked, the vessels are no longer guided to the appropriate layers and instead migrate directly past the inner nuclear layer into the normally avascular photoreceptor layer [11]. Thus, similar to the superficial plexus, mechanisms involving specific expression of growth factors and cell-cell adhesion molecules are also important for initiation and guidance of the deep retinal vascular plexuses. Bone marrow derived cells also rely on similar cues to target to sites of retinal neovascularization, even ahead of the developing endogenous vessels, further supporting the existence of preexisting guidance cues [12]. Normally, these Lin– bone marrow-derived cells will target to astrocytes and the developing vasculature (Fig. 2.2). However, when R-cadherin mediated adhesion is blocked, many of these cells lose targeting abilities and instead migrate through the retina and mistarget to the subretinal space [12] similar to the mistargeting of the endogenous vasculature (Fig. 2.7).
2.7 Vascular Maturation
As the characteristic retinal plexuses are formed, they must undergo final maturation before vascular development is complete. This involves appropriate mural cell recruitment, and remodeling of the vascular plexus. Mural cell recruitment occurs almost con-
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Fig. 2.7. Formation of the characteristic deep vascular plexuses is mediated by filopodia and R-cadherin mediated cell-cell adhesion.
a Filopodial extensions are observed at the
endothelial tips as vessels branch and migrate from the superficial plexus to the deep vascular plexuses. b R-cadherin expression correlates spatially and temporally with deep vascular plexus formation. c As vessels branch from the superficial plexus and migrate toward the deep retina, normal R-cadherin guidance cues guide the vessels to the normal deep vascular plexus. d The normal deep retinal plexus forms at the outer edge of the inner nuclear layer (left), but when R-cadherin adhesion is
blocked (right panel), these guidance cues are lost and the deep vascular plexus fails to form normally resulting in the abnormal formation of subretinal vessels (green astrocytes, red blood vessels, blue DAPI nuclei). e Lin-bone marrow derived progenitor cells (green) also use R-cadherin mediated adhesion to target to the three vascular plexuses (top). When R-cadherin adhesion is blocked, targeting of the bone marrow-derived progenitors is also lost and these cells become abnormally localized within the subretinal space (bottom). (a, b images adapted from [11]; c image adapted from [10]; d, e image adapted from [12])
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comitantly with neovascular formation [9]. As the new vessels grow, endothelial cells secrete platelet derived growth factor (PDGF). Mural cells respond to this signal through receptors on their cell surface and are thereby recruited to the neovessel surface. The lack of functional PDGF is embryonic lethal due to numerous microvascular aneurysms thought to be caused by a lack of pericyte association with the developing vasculature [24]. Similar to the importance of VEGF localization during the endothelial cell guidance, PDGF localization is also important for appropriate mural cell recruitment. PDGF also has a heparin binding motif that prevents its diffusion away from the neovessels. This helps localize the recruited mural cells to the neovessel surface. Removal of the heparin-binding domain from PDGF results in a lack of pericyte recruitment in the developing retinal vasculature and these vessels eventually regress leading to several vascular abnormalities.
Deletion of the PDGF Heparin Binding Motif Results In:
Loss of mural cell recruitment in the developing retina (fewer pericytes)
1elayed vascular development
Abnormal vessels with irregular branching
Excessive remodeling Vascular leakiness
2.8 Vascular Pruning Mechanisms
The newly formed retinal vascular plexuses are initially highly dense networks of vessels that must be pruned during the later stages of vascular maturation. This pruning occurs as a result of the recruitment and activity of activated leukocytes [21]. A brief period of hyperoxia results from the initial overly dense vascular networks. This causes upregulation of intercellular cell adhesion molecule 1 (ICAM-1) on the lumen surface of the endothelial cells. CD18 molecules on circulating leukocytes adhere to ICAM-1 on the sides of the vessels leading to extravasation and activation of these cells. Through Fas-L mediated apoptosis, these cells then cause the regulated cell death of certain endothelial cells resulting in the mature, pruned retinal vasculature observed in a normal, healthy adult.
Vascular Pruning Activities:
Mural cell recruitment during vascular development
Hyperoxia caused by the dense neovascular plexuses formed during early retinal vascular development
Upregulation of ICAM-1 on the endothelial cells’ lumen surface
Recruitment and activation of circulating leukocytes through CD18/ICAM-1 interactions Regulated endothelial cell death leading to a mature, pruned vascular network. Selective mural cell association may help stabilize certain vessels and regulate the extent of vascular regression.
2.9Mouse Retinal Vascular Development as a Model for General Vascular Development
Investigating the mechanisms of vascular development can be quite difficult due to the fact that most vascular systems develop during embryogenesis. In vitro assays, while important, often fail to replicate the intricate nature of neovascularization. For in vivo studies, the importance of specific factors has historically been determined by analyzing the effect of genetic knock-downs. However, this is complicated by natural compensatory mechanisms that often result in little or no phenotypic differences, even when factors known to be important for vascular development are deleted. Also, it is very difficult to administer exogenous compounds to developing fetuses in a controlled manner, making it difficult to assess the roles of particular factors using molecular agonists or antagonists.
The retina, particularly in non-primate species, has several advantages that overcome many of the experimental complications normally associated with in vivo studies of developmental vascularization, allowing researchers to study the molecular events of developmental neovascularization in its natural context.
Essentials
In non-primates, retinal vascular development occurs postnatally
Direct intravitreal injections of exogenous molecules are possible
Retinal vascular development is highly organized
–Allows even subtle alterations in vascular patterning to be observed more easily
–Mediates specific studies of vascular
guidance mechanisms
Retinal vascular development is temporally consistent
–Facilitates specific studies regarding different phases of retinal vascular development (super-
ficial vs. deep plexus, etc.)
–Facilitates analysis of the effects of exogenous proor anti-angiogenic molecules
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born animals to hyperoxia (or to alternating hypero- |
Utilization of vascular targeting bone mar- |
xia and hypoxia) prompts regression or delay of reti- |
row-derived progenitor cells facilitates anal- |
nal vascular development, followed by abnormal |
ysis of the effects of specific knock-ins or |
neovascularization upon return to normal oxygen |
knock-downs |
levels (Fig. 2.8). These models mirror the events that |
–Faster and more simple than engineering occur during retinopathy of prematurity (ROP), a and producing various transgenic mouse condition involving pathological neovascularization
colonies
–Use of siRNA or other non-genetic methods of altering protein expression is applicable to multiple species
2.10Use of Retinal Vascular Development as Models for Clinical Ocular Neovascularization
that can affect premature infants [2, 19, 38]. Retinopathy of prematurity will be discussed extensively in later chapters. In recent years, the use of this model has been extended to the general study of ischemic vasculopathies and related anti-angiogenic interventions, and it is now used extensively in both basic and applied research environments.
References
Because of the inherent advantages, and the similarities between developmental and pathological angiogenesis, many aspects of retinal vascular development have been adapted as models for clinical ocular neovascularization. These models are used for various preclinical studies ranging from identifying mechanisms associated with vascular retinopathies, to testing potential angiostatics for clinical use.
2.10.1 Mouse Retinal Angiogenesis Model
In the neonatal mouse, the retinal vasculature develops during the first 3 weeks after birth, with the superficial plexus forming during the first 10 days. The deep vascular plexus begins formation during the 2nd week with sprouts budding from the superficial plexus around postnatal day 8 (P8) and a fully dense, albeit not yet fully remodeled, plexus in place by P12. By injecting various angiostatic compounds at P7–P8, either systemically by intravenous injection, or locally by intravitreal or subretinal injection, and assessing the effects on the formation of the deep vascular plexus, the activity of these compounds can be analyzed relatively easily in vivo (Fig. 2.8). Importantly, by analyzing the effects on the already established superficial plexus, one can also assess whether these compounds may adversely affect pre-estab- lished normal retinal vessels. This model has been used extensively to test various angiostatic and combinations of angiostatic molecules [13, 30].
2.10.2 Oxygen-Induced Retinopathy
By altering the oxygen levels to which the neonatal mouse (or rat) pups are exposed, one can also manipulate the retinal vascular development in a way that mimics many aspects of clinical disease. In several animal species, including the kitten, the beagle puppy, the rat, and the mouse [25], exposing new-
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a
Fig. 2.8. Clinical utility of mouse models of developmental retinal vascularization. a Anti-angiogenic factors can be injected at postnatal day 7, just before formation of the deep vascular plexus, and the effect on the formation of the deep vascular plexus can be assessed
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Retinal Angiogenesis and Growth Factors |
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General Concepts of Angiogenesis and |
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Vasculogenesis |
C. Ruiz de Almodovar, A. Ny, P. Carmeliet
Core Messages
Vasculogenesis in the embryo is a result of mesoderm-derived endothelial precursor cells There is a tissue specific endothelial cell differentiation resulting in heterogeneous tightjunction formation and fenestration properties. The tissue specific differentiation of
endothelial cells is regulated by a variety of growth factors
Angiogenesis is the formation of blood vessels from existing ones and includes spouting, bridging, and intussusceptive growth from preexisting vessels, remodeling and pruning
3.1.1 General Introduction
The vasculature is the first organ to arise during development. Blood vessels run through virtually every organ in the body, ensuring metabolic homeostasis by supplying oxygen and nutrients and removing waste products. Consequently, a dysfunction of blood vessels compromises normal organ performance. This in turn may lead to congenital or acquired diseases, disability or even death. The lymphatic system develops in parallel but secondary to the blood vascular system. It serves an essential function in absorbing and transporting tissue fluid and extravasated proteins and cells back to the venous circulation. Understanding the principles of how blood and lymph vessels form and which angiogenic factors are involved might provide novel attractive opportunities for treatment of angiogenic disorders.
3.1.2 Angiogenic Disorders
Dysregulation of vessel growth, either because of an excess or an insufficient number of vessels, has a major impact on our health and contributes to the pathogenesis of many disorders. The first identified and best known angiogenic disorders are cancer, arthritis, psoriasis and blinding retinopathy [90, 162]. However, there are numerous other inflammatory, allergic, infectious, traumatic, metabolic or hormonal disorders, which are characterized by excessive vessel growth including atherosclerosis, restenosis, transplant arteriopathy, warts, allergic
dermatitis, scar keloids, peritoneal adhesions, synovitis, osteomyelitis, asthma, nasal polyps, choroideal and intraocular disorders, retinopathy of prematurity, diabetic retinopathy, leukomalacia, AIDS, endometriosis, uterine bleeding, ovarian cysts, ovarian hyperstimulation, liver cirrhosis, nasal polyps and the list is still growing (Table 3.1.1) [41, 43, 45]. In obesity, adipose tissue may also show excessive vessel growth. A high fat diet induces an angiogenic gene program in fat [191] and angiogenic factors stimulate adipogenesis, while treatment of obese mice with anti-angiogen- ic agents results in weight reduction and adipose tissue loss [276]. Viral and bacterial pathogens carry angiogenic genes of their own [218], or induce the expression of angiogenic genes in the host [122]. The human herpesvirus 8 transforms endothelial cells (ECs) and causes Kaposi’s sarcoma in HIV-1 infected AIDS patients. Infectious diseases, such as chronic airway inflammation, are also angiogenic [21].
Vessel pruning is a physiological mechanism to match perfusion with metabolic demand when the nascent vasculature consists of too many vessels. However, vessel regression also contributes to the pathogenesis of numerous disorders (Table 3.1.2). For instance, lower levels of the primary angiogenic factor, vascular endothelial growth factor (VEGF), cause organ dysfunction in pregnant women with preeclampsia [213]. A progressive loss of the microvasculature underlies many age-related diseases. In the skin, age-dependent reductions in vessel density and maturation cause vessel fragility leading to the development of purpura, telangiectasia, pallor, angioma and venous lake formation [54]. In old age, a pro-