Angiogenesis and hypertensive retinopathy -
The rapid persistent rise in BP in malignant hypertension results in arteriolar constriction that eventually leads to necrosis of the arteriolar wall smooth muscle cells decreasing their ability to constrict. This in turn results in failure of autoregulation and thus to the transmission of the high BP to the endothelium breaking down the blood-retina barrier [ 10 ], which translates to features of ischemia and leakage that are seen in hypertensive retinopathy.
It is well known that young individuals are more susceptible to hypertensive choroidopathy. This is explained by the fact that their blood vessels are more pliable and flexible than older people because of the absence of sclerosis [ 10 ].
Of note, all the patients described in the cases of hypertensive retinopathy with retinal neovascularization were relatively young.
This may as well be explained by the pliable nonhyalinized retinal vessels in the young. Moreover, retinal vessel autoregulatory mechanisms can maintain vascular tone longer than choroidal vessels, and thus, the retina is expected to withstand high BP for a longer duration than the choroid before developing significant ischemia [ 10 ].
This and the wide availability of oral antihypertensive medications may explain the rarity of proliferative hypertensive retinopathy.
Controlling BP remains the most important step in the management of hypertensive retinopathy. In the cases associated with neovascularization, however, PRP or intravitreal anti-VEGF injections or both should be undertaken to induce regression of the neovascularizations and potentially prevent further complications.
We preferred bilateral PRP over anti-VEGF intravitreal injections in our case due to the socioeconomic status and the noncompliance of the patient. These patients should be followed closely as they could show recurrence of neovascularization that would require repeating the treatment.
This case, in addition to the few previous reports, provides evidence supporting the notion of retinal neovascularization secondary to severe systemic hypertension. The fact that malignant hypertension might cause such a condition with devastating sequelae should encourage ophthalmologists to follow similar cases closely and to assume a more active role in their management.
Malignant hypertension can rarely cause proliferative retinopathy with its devastating sequelae. Managing hypertensive retinopathy with antihypertensives alone, as is the current standard of care, might not be enough.
Early recognition and timely treatment are of paramount importance and require a close multidisciplinary management. This case report was conducted according to good clinical practice.
The authors state that they have full control over all primary data and have no ethical conflicts to disclose. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
The contributions of the authors were in line with the ICMJE authorship criteria. diagnosed the condition and performed the literature search, data collection and drafted the manuscript. provided ophthalmic care and critically reviewed and revised the manuscript.
reviewed the patient from the rheumatology point of view and critically reviewed and revised the manuscript. All the authors contributed to data interpretation, and all the authors read and approved the final manuscript. Sign In or Create an Account.
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Funding Sources. Author Contributions. Article Navigation. Case Reports July 01 Hypertension as an Unusual Cause of Proliferative Retinopathy: Case Report and Literature Review Subject Area: Ophthalmology.
Rami Hasan Saleem Abu Sbeit X. Rami Hasan Saleem Abu Sbeit. a Department of Ophthalmology, Hamad Medical Corporation, Doha, Qatar. This Site. Google Scholar. Osman Abdelzaher Mohammed ; Osman Abdelzaher Mohammed. Laith Ishaq Alamlih Laith Ishaq Alamlih. b Division of Rheumatology, Department of Medicine, Hamad Medical Corporation, Doha, Qatar.
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View large Download slide. Table 1. Summary of documented cases with retinal neovascularization associated with hypertension. View large. View Large. The authors have no conflicts of interest to declare. Open access funding provided by the Qatar National Library.
Search ADS. Bilateral hypertensive retinopathy complicated with retinal neovascularization: panretinal photocoagulation or intravitreal anti-VEGF treatment? Hypertensive crisis with massive retinal and choroidal infarction: a case update.
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Survival of a Rhino-Orbital-Cerebral Mucormycosis Patient after Localized Combination Liposomal Amphotericin B Medications: A Case Report. Related Articles. Online ISSN Karger International S. Karger AG P. Vascular endothelial growth factor VEGF blockers have evolved over time for the treatment of retinal neovascularization.
However, several limitations to anti-VEGF interventions exist. This review focuses on the tight cross talk between angiogenesis and inflammation during PDR and describe how the chick embryo chorioallantoic membrane CAM assay may represent a cost-effective and rapid in vivo tool for the study of the relationship between neovascular and inflammatory responses elicited by the vitreous humor of PDR patients and for the screening of novel therapeutic agents.
Retinal and choroidal neovascularization are the leading causes of visual impairment in various ocular pathologies, including retinal vein occlusion, age-related macular-degeneration, retinopathy of prematurity and diabetic retinopathy DR.
DR is one of the main complications of diabetes mellitus and it represents the major cause of vision loss in the working-age population 1. At present, million adults are estimated to be living with diabetes worldwide, a number projected to rise to million by 2.
In the earlier stages, the disease manifests as non-proliferative microaneurysms; then, it progresses to proliferative diabetic retinopathy PDR.
Hallmarks of PDR are the presence of hard and soft exudates, neovascularization and hemorrhages. The retinal microvasculature is progressively damaged by the disease, resulting in various events such as retinal ischemia, upregulation of hypoxia inducible factor-1 HIF-1 , and vascular endothelial growth factor VEGF secretion, possibly progressing to PDR, which is diagnosed according to the presence of vascular lesions e.
Inflammation and angiogenesis are two of the main factors that contribute to PDR. During the disease, inflammation and neovascularization establish a strict cross talk, with inflammation promoting neovascularization and vice versa [see 5 — 8 and references therein].
Interestingly, clinical evidence shows a lower occurrence of DR in diabetic patients treated with salicylates for rheumatoid arthritis 9. Accordingly, anti-inflammatory drugs could be beneficial for managing retinal neovascularization. Indeed, the progression of pathological neovascularization and of diabetic macular edema may be reduced by the administration of corticosteroids e.
Even though, corticosteroids could be effective in improving or at least stabilizing visual acuity, these results are often temporary and administration of corticosteroids may be associated with adverse effects, such as increased intraocular pressure and cataract formation 10 — Laser photocoagulation is a widely used technique for treating retinal neovascularization, allowing long-term regression.
However, the identification of VEGF as a key mediator in the pathogenesis of DR, able to promote both angiogenesis and vascular permeability, led to the establishment of anti-VEGF agents as an alternative line of treatment 4.
Clinical and experimental evidence suggests that intraocular levels of VEGF are increased during retinal ischemia, resulting in the breakdown of the blood-retina barrier, enhanced vascular permeability, and neovascularization A recent meta-analysis of aggregate data has indicated that anti-VEGF pharmacotherapy is associated with superior visual acuity outcomes and less PDR-related complications when compared to retinal laser photocoagulation However, limitations do exist in the use of anti-VEGF agents.
Indeed, due to their brief duration of action, anti-VEGF drugs need to be frequently administered via intravitreal injection, possibly resulting in adverse side effects i.
Furthermore, a large percentage of patients do not respond to anti-VEGF drugs or exhibit a poor response. Supposedly, this limited efficacy may depend on the activation of other pathways promoting ocular angiogenesis as a consequence of the local production of various pro-angiogenic and pro-inflammatory factors [reviewed in 15 — 17 ].
Therefore, a better knowledge of the pathogenesis of DR is required, in order to clarify the relationship between inflammation and angiogenesis during the disease progression. Indeed, a better understanding of their role in the disease could allow for the identification of novel anti-inflammatory approaches targeting retinal angiogenesis.
In this frame, the implementation of new methods that could allow the discovery of novel strategies targeting molecular pathways involved in ocular neovascularization is essential. To achieve this aim, many pharmacological studies have been carried out in various in vitro and ex vivo assays, suitable for the screening of small anti-angiogenic compounds 16 , In addition, mouse models have been established in order to investigate retinal angiogenesis 19 , However, the use of these models is hindered by various limitations The chick embryo chorioallantoic membrane CAM has been proposed as a valid alternative animal model for the investigation of the mechanisms underlying physiological and pathological angiogenesis Angiogenesis is a complex multi-step process.
Various events are necessary for angiogenesis to occur, including the interaction between cell surface receptors, soluble factors, and extracellular matrix components. Several cell types are also required, with endothelial cells playing a major role The formation of neovessels has been thoroughly investigated and described in several insightful reviews 24 — Briefly, hypoxia promotes the release of angiogenic factors, such as VEGF, responsible for inducing the detachment of pericytes from the vessel wall, which weakens the interactions among endothelial cells and increases vascular permeability Moreover, pro-angiogenic molecules directly increase vascular permeability by disrupting adherens junctions and by inducing the phosphorylation of vascular endothelial-cadherin, thus allowing serum proteins extravasation from the vascular lumen After all these steps have been accomplished, the production of pro-angiogenic mediators decreases, the neovessels are remodeled by the blood flow itself, and endothelial cells return to their quiescent condition During diabetes, hyperglycemia acts on retinal endotelium, promoting the activation of interconnected biochemical pathways, including the polyol sorbitol-aldose reductase 32 and hexosamine 33 pathways, enhanced production of advanced glycation end products 34 and reactive oxygen species ROS 35 , and activation of protein kinase C 36 , 37 , poly ADP-ribose polymerase 38 , and of the renin-angiotensin system All of these events contribute to increasing oxidative stress, which, in turn, triggers neovascularization, inflammation, and early neurodegeneration.
Moreover, hyperglycemia affects retinal mitochondria, which become dysfunctional. Consequently, the production of ROS is increased, damaging DNA, promoting the release of cytochrome C, and resulting in endothelial cell apoptosis Another important feature of the vascular dysfunction that occurs during DR is the loss of retinal pericytes, which further destabilizes endothelial cells and alters perfusion The tight interaction between pericytes and endothelium is disrupted by the progressive thickening of the basement membrane that, together with systemic and local hypertension, promotes pericyte apoptosis.
These hyperglycemia-induced alterations are considered one of the primary events in the pathogenesis of DR and they are followed by other dysfunctions, such as retinal hyperpermeability, thickening of the basal endothelial membrane, and activation of a strong inflammatory response.
Another hallmark of DR is the presence of micro-occlusions in the retinal microvasculature Endothelial cells upregulate the expression of the intracellular adhesion molecule 1 ICAM-1 , which is responsible for mediating the adhesion of leukocytes to the endothelium The constriction of major arteries and arterioles leads to areas of decreased perfusion associated with an upregulation of HIF-1, which levels are elevated in the vitreous of PDR patients 44 , HIF-1 upregulates several growth factors, cytokines, and chemokines, leading to retinal neovascularization These HIFregulated factors include various pro-angiogenic molecules, such as VEGF, erythropoietin, fibroblast growth factor 2 FGF2 , insulin-like growth factor-1, stromal cell-derived factor-1, platelet-derived growth factor, tumor necrosis factor α TNFα and interleukins ILs 17 , 47 — In addition, many anti-angiogenic mediators are downregulated, including angiostatin and pigment epithelium-derived factor and decreased levels of these molecules have been reported in the vitreous of diabetic patients A tight cross talk between inflammation and angiogenesis takes place in several physiological and pathological conditions 51 , Inflammatory cells are responsible for the production of various molecules, including growth factors, cytokines, and proteases.
All of these mediators contribute to neovessel formation Moreover, activated endothelial cells express pro-inflammatory molecules that mediate the recruitment and the activation of white blood cells 54 , Several signaling pathways are shared by neovascularization and inflammation processes Indeed, various chemokines might exert a double function by promoting leukocyte adhesion to the endothelium and stimulating endothelial cell proliferation In addition, several pro-inflammatory cytokines, including IL6, IL1α, IL1β, osteopontin, high mobility group box-1, and TNFα, may directly activate angiogenesis by acting on endothelial cells.
These same cytokines also promote angiogenesis indirectly by activating the production of more pro-angiogenic factors by leukocytes and endothelium 58 — Conversely, endothelial cells stimulated by the pro-angiogenic factors VEGF and angiopoietin-1 increase the expression of cell adhesion molecules, as well as the production of inflammatory factors 61 , A further example of the cross talk that occurs between angiogenesis and inflammation is provided by the capacity of pro-inflammatory stimuli to induce the upregulation of HIF-1 α gene expression via the activation of the canonical nuclear factor κB NF-κB pathway, a key regulator of innate immune, inflammatory and angiogenic responses In addition, oxygen-sensing hydroxylases may confer hypoxic sensitivity to both HIF and NF-κB pathways concurrently Thus, a tight interaction exists between HIF and NF-κB signaling that leads to the production of inflammatory and angiogenic mediators under hypoxic conditions, including VEGF Inflammation is a crucial event for the development of DR.
It is especially relevant during the initial stages of the disease, when inflammation activates transcriptional factors and induces the increased expression of both pro-inflammatory and pro-angiogenic mediators 66 , Retinal inflammation is closely associated with neovascularization.
Indeed, during inflammation, retinal microglia become activated and release cytokines and pro-angiogenic mediators 68 responsible for the maintenance of chronic inflammation in the retina 7 , Prolonged inflammation is extremely detrimental and it contributes to damaging retinal vasculature, promoting the formation of neovessels as well as the development of macular edema 7 , Moreover, inflammation may be involved in retinal neurodegeneration, which is frequently observed in DR patients 7 , New insights into the exact role of inflammation in the pathogenesis of DR may allow for the identification of new molecular pathways and for the discovery of novel therapeutic targets.
The association of anti-angiogenic and anti-inflammatory drugs may therefore be beneficial for treating DR 71 — The chick embryo CAM is a vascular membrane formed by the fusion of the mesodermal layers, the allantois, and the chorion that appears at day 3—4 of incubation. It consists of three layers, ectoderm originating from the chorion and attached to the shell membrane , mesoderm represented by the fusion of the somatic mesoderm from the chorion and the splanchnic mesoderm from the allantois , and endoderm originating from the allantois and facing up the allantoic cavity The middle mesodermal layer is enriched in stromal components and blood vessels connected with the embryonic circulation by allantoic arteries and veins Figure 1.
Figure 1. The chick embryo and its chorioallantoic membrane. A Schematic drawing of the general structure of a 5 day old chick embryo in the egg and the three-tissue layers of the chick chorioallantoic membrane CAM. B Semithin section of the CAM of a 12 day old chick embryo showing the chorionic epithelium ch , the vascularized mesoderm m , and the allantoic epithelium al.
C 5 day old chick embryo photographed in ovo [ B,C , reproduced from 75 ]. By 16 days of incubation, the CAM has grown so large that it completely covers most of the yolk sac and becomes adjacent to the shell membrane.
The surface area of the CAM, which measures about 6 cm 2 on day 6, increases to 65 cm 2 by day 14 The large surface extension and its position confer to the CAM a respiratory function through the pores in the eggshell As shown by Schlatter et al.
In the first phase, multiple capillary sprouts invade the mesenchyme, fuse, and form the primary capillary plexus. During the intermediate phase, tissue pillars, expression of intussusceptive angiogenesis, replace capillary sprouts.
In the third phase, the growing pillars increase in size to form intercapillary meshes [see 77 , 78 for light microscopy and microvascular corrosion cast images of the three-phase process of the vascular development of the CAM].
In the early phase, the blood vessels are immature as they are not covered by smooth muscle cells and the basal lamina is incomplete. This initial structure allows the blood vessels to spread into the mesoderm, where they rapidly expand until day 8 to create a capillary plexus.
The capillary plexus becomes close to the overlying chorionic epithelial cells, where it mediates gas exchange with the outer environment by receiving oxygen and eliminating carbon dioxide.
Blood vessel proliferation continues until day Then, it declines rapidly until day 18 when the vasculature attains its final arrangement up to hatching The CAM is a favored system for the in vivo study of physiological and pathological angiogenesis.
Its extensive vascularization and easy accessibility make the CAM assay a simple experimental platform to investigate the efficacy and mechanisms of action of pro- and anti-angiogenic molecules.
The assay is performed by grafting the materials to be tested onto developing CAM through a window cut in the eggshell. The embryogenesis starts as soon as the fertilized eggs are placed horizontally in an incubator at 37°C.
The physiological environment for the CAM is guaranteed by working at controlled temperature and humidity. On day 3, after removing of approximately 5 ml of albumen, a window is opened in the shell to detach the CAM from the shell itself and to make the vascular surface accessible.
This technique has the advantage of high viability in long-term incubation assays and allows the use of the embryos until just before hatching at day 21 , its disadvantages being represented by a limited area for manipulation and observation To avoid the disadvantage of the limited area of work, it is possible to transfer the embryo with its extraembryonic membranes into a Petri dish on day 3—4 of incubation.
This experimental setting favors CAM development at the top of the Petri dish as a flat membrane on which multiple tests can be grafted In addition, this ex ovo system is more suitable for live imaging than in ovo techniques and it allows the quantification of the response over a full area of the CAM by testing simultaneously a large number of samples.
However, long-term viability is often shorter than in ovo , and more care is needed to avoid embryo dehydration. Several protocols have been developed for the release of molecules to be tested in the CAM assay. Macromolecules and low molecular weight compounds are placed onto the CAM using silostatic or silicon rings, methylcellulose disks, filters, plastic rings, or sponges.
Sponges can be made in collagen or gelatin and are suitable also for testing the effects of cell xenografts Usually, an angiogenic response occurs 72—96 h after stimulation. The pro-angiogenic activity of a compound results in an increased blood vessel density around the implant, with newly formed blood vessels arranged in a radial pattern like the spokes of a wheel.
On the contrary, when a compound with an anti-angiogenic activity is tested, the blood vessels become less numerous around the implant, and occasionally they disappear. Different semi-quantitative and quantitative morphological and molecular methods have been developed to evaluate pro- or anti-angiogenic responses in the CAM assay at macroscopic and microscopic levels.
Quantification of the CAM vasculature can be performed with the use of extensive vessel-counting methods based on visual examination and manual vessel counts or global measurements of the spatial pattern and distribution by algorithms.
At the end of the assay, the membranes can be processed for in-depth analysis by immunohistochemistry preceded by paraffin embedding, or for ultrastructure analysis by electron microscopy. Moreover, fresh CAM samples can be processed for molecular studies, including the determination of DNA amount, selected protein and collagen content by Western blotting or spectrophotometric based-methods , and gene expression analysis by quantitative RT-PCR.
The immune system of the chick begins to develop during the embryonic life Classically, innate responses are essential in the earliest phases of microbial invasion, until adaptive responses B and T cell-mediated become active to clear the infection.
The chick immune system consists of B and T cells that control humoral and cell-mediated immunity, respectively. The B cells differentiate in the bursa of Fabricius, whereas T cells differentiate in the thymus 83 , The presence of T cells can be first detected at day 11 and of B cells at day 12 85 , and by day 18 chick embryos become immunocompetent 86 , The first line of defense against bacterial pathogens in the chick embryo is represented by heterophils These rounded cells release microbicidal agents, including ROS, proteolytic enzymes, and microbicidal peptides from their cytoplasmic granules.
Heterophils present two types of granules. The primary granules are fusiform, display a central body that may be proteinaceous, and appear brick-red in color after Romanowsky stains. The secondary granules are rounded, less abundant, and smaller compared to the primary ones. Unlike mammalian neutrophils, chick heterophils are devoid of myeloperoxidase The chick embryo yolk sac produces the first generation of macrophages.
Chick embryonic macrophages, identified at embryonic day 12—16 in the spleen and liver, recognize and phagocytize microbial antigens In chickens, T-cell membrane protein 4 TIM4 is a receptor expressed primarily by macrophages, binds to phosphatidylserine, and most likely participates in the recognition and clearance of apoptotic cells Hu and colleagues applied anti-chicken TIM4 monoclonal antibodies in combination with colony stimulating factor 1 receptor reporter transgenes to dissect the function of TIM4 in the chick They demonstrated that TIM4 was present on the large majority of macrophages during development in ovo and to be expressed also by other cells with phagocytic activity, such as dendritic cells, after hatching An inflammatory response may be induced in the CAM assay through different stimuli.
These cells can deliver several pro- and anti-inflammatory factors and cytokines, as well as important modifiers of the extracellular matrix [i. Figure 2. Inflammatory infiltrate in the chick embryo CAM. A Naphtol-AS-D-chloroacetate esterase-positive macrophages arrowheads in intravascular a and perivascular position b in the CAM mesoderm.
B Macrophages m and a lymphocyte ly are recognizable at ultrastructural level around the endothelium e beneath the chorion ch.
Note an increasing number of microvessels arrows and of the inflammatory infiltrate inside the marked area [reproduced from 91 ]. Nuclear staining with DAPI in blue. A systematic study on the interplay between angiogenesis and inflammation, using different carrier materials placed on the CAM e.
The reactions induced by these materials were compared with those induced by natural egg materials white eggshell membrane, coagulated albumen, and yolk. In all the cases, the CAM reacted with the proliferation of ectodermal cells, fibroblasts, and blood vessels, resulting in a highly capillarized granulation tissue.
Accordingly, the CAM has been used as an in vivo model to study wound repair This model consistently reproduces all the phases observed in adult wound healing, including re-epithelization, angiogenesis, inflammation, and fibronectin deposition, resulting in scar formation The CAM has been used also as a model for the evaluation of inflammatory effects by tissue tolerable plasma for the determination of the optimum parameters for treatment of chronic wounds.
The response patterns, represented by granuloma development with associated angiogenesis , hemorrhages, coagulation, and contracture, were alleviated when hydrocortisone was added immediately after plasma treatment The presence of a mononuclear cell infiltrate has been observed also in osteopontin OPN -treated CAMs and responsible, at least in part, for the neovascular response triggered by this cytokine Mononuclear cells were frequently found to encircle microvessels located at the boundary between the OPN-loaded sponges and the surrounding CAM mesenchyme, and the presence of mononuclear cells and lymphocytes has also been demonstrated at the ultrastructural level Similarly, Andrés and colleagues demonstrated that FGF2-loaded alginate beads trigger a robust angiogenic response when implanted on the CAM surface In parallel, the presence of an inflammatory cell infiltrate in the stroma among the newly formed blood vessels was revealed by May Grünwald-Giemsa staining of the treated membranes.
The results showed that both drugs were able to inhibit the angiogenic response triggered by FGF2 In this frame, Sung et al. examined the in vivo effects of the sequential delivery of dexamethasone followed by VEGF on the immune response and vascular network formation in the CAM assay.
Cross-section images of control CAMs showed very few inflammatory cells, mostly macrophages and heterophils. In contrast, an abundant presence of inflammatory cells, fibroblast encapsulation, and swelling edema were found in the tissue surrounding the VEGF implant that were inhibited by dexamethasone Together, these data indicate that the chick embryo CAM represents a platform suitable for the study of the cross talk between angiogenesis and inflammation.
The use of the chick embryo CAM for the study of retinal vascular pathologies dates back to the early' 80s. Glaser and colleagues utilized the CAM to investigate the vasoproliferative activities of several mammalian tissue extracts i. They observed a potent vasoproliferative response when pellets containing retinal extracts were applied on the top of the CAM, while other adult tissues resulted ineffective With a similar approach, Okamoto and colleagues demonstrated that extracts derived from rabbit retina, iris-ciliary body, and optic nerve exerted an angiogenic activity on CAM, with retinal extracts inducing the strongest effect On these bases, the CAM assay was applied for testing angiogenic factors extracted from both cat and bovine retinas , and Prost compared the angiogenic activity of the detached retina with that of the normal attached retina, demonstrating that the detached retina exhibits a stronger angiogenic activity The first experimental evidence that the CAM assay could provide useful information for the study of DR was obtained by Hill and colleagues.
In this study, the vitreous humor from PDR patients promoted the proliferation of CAM blood vessels, while vitreous from non-diabetic patients was ineffective Thereafter, Taylor et al.
isolated an endothelial cell-stimulating angiogenic factor from the human vitreous and demonstrated its pro-angiogenic activity in the CAM assay In addition to neovascular studies, the CAM has been used as a substrate for maintaining mammalian retinal explants in culture and as a model for testing novel surgical procedures for cutting and coagulating the retinal vasculature Vitreous humor obtained via pars plana vitrectomy from PDR patients has been shown to exert significant biological responses when delivered in vitro and in vivo to different cell types in various pre-clinical experimental models [reviewed in ].
Thus, the study of the biological activity of PDR vitreous may provide further insights into the relationship between inflammation and angiogenesis.
It has been demonstrated that PDR vitreous contains high levels of both pro-inflammatory and pro-angiogenic factors 17 , As a consequence, the biological activity exerted by PDR vitreous in in vitro and in vivo models depends on the balance between all the mediators that have accumulated in the ocular fluid during the progression of the disease and that are present at time of harvesting.
Moreover, PDR vitreous can be employed in several experimental models in order to screen and characterize drugs with potential pharmacological applications. In this frame, we have shown that PDR vitreous induces a pro-angiogenic response in endothelial cells whereas vitreous fluid obtained from macular hole patients was ineffective — Indeed, PDR vitreous fluid activates in vitro all the steps of the angiogenic process, including endothelial cell proliferation, motility, sprouting, and tube formation.
At the same time, PDR vitreous induces a pro-inflammatory activation of endothelial cells characterized by the nuclear translocation of the pro-inflammatory transcription factors NF-κB and CREB, ROS production, disruption of endothelial intercellular junctions, upregulation of the cell adhesion receptors vascular cell adhesion protein 1 and ICAM-1 and consequent increase of leukocyte adhesion.
Alginate beads loaded with 2. After 72 h, several neovessels moving toward the graft were detected. Moreover, the beads containing PDR vitreous attracted a significant population of mononuclear cells, which was absent in controls Significantly, the number of neovessels was correlated with the extent of the inflammatory infiltrate Figure 3.
Figure 3. A Macroscopic pictures of the CAM at day 12 of incubation, showing a silicon ring containing vehicle control and a PDR vitreous sample. Note a strong angiogenic response in the experimental sample as compared to the control one.
B Histological sections of the marked areas evidenced in A. Note a strong angiogenic response and a dense inflammatory reaction in the experimental sample as compared to the control one.
C, D Morphometric quantification of the inflammatory infiltrate area C and of the microvascular density area D. E Correlation between microvascular density and inflammatory infiltrate induced by PDR vitreous in the CAM assay.
It is worth noticing that a high variability in the angiogenic and inflammatory responses was observed when vitreous samples obtained from 10 patients with PDR were individually applied to the top of the CAM Since the more angiogenic samples were able to trigger a more significant inflammatory response, these data support the notion that angiogenesis and inflammation are closely related processes during PDR.
Accordingly, treatment with hydrocortisone was able to reduce drastically the angiogenic response and the recruitment of inflammatory cells induced by PDR vitreous in the CAM assay.
Thus, inflammation appears to play a significant role in the angiogenic activity exerted by PDR vitreous. Figure 4.
Correlation between the angiogenic and inflammatory responses triggered by individual PDR vitreous samples in the chick embryo CAM. Vitreous samples from 10 PDR patients were individually tested in the CAM assay.
N -formyl peptide receptors FPRs belong to a class of pattern recognition receptors that are involved in controlling inflammation, angiogenesis, tissue repair, and innate immune responses The tetrapeptide Ac-L-Arg-Aib-L-Arg-L-Cα Me Phe-NH2 UPARANT blocks urokinase-type plasminogen activator receptor uPAR -dependent cell signaling by interfering with the complex cross-talk among FPRs, uPAR, and integrins.
Accordingly, UPARANT competes with N -formyl peptides for the binding to FPRs and inhibits VEGF-driven angiogenesis by preventing FPR activation Recent studies have shown that UPARANT exerts an anti-angiogenic and anti-inflammatory activity when tested in animal models of oxygen-induced retinopathy by inhibiting ocular neovascularization and by lowering the levels of inflammatory molecules Accordingly, UPARANT successfully inhibited the formation of novel blood vessels promoted by 16 out of 20 individual samples of PDR vitreous in the CAM assay.
Again, its anti-angiogenic effect was linearly correlated with a reduced inflammatory infiltrate, suggesting that FPR activation may play a non-redundant role in promoting neovascularization during PDR Three FPRs have been identified in humans FPR1—FPR3 , characterized by different ligand properties, biological function and cellular distribution Among them, FPR3 appears to mediate pro-angiogenic responses in human endothelial cells It must be pointed out that the murine genome contains eight FPR-related sequences whereas the presence of FPR gene ortholog s in birds is more uncertain.
Indeed, a cell surface protein immunoreactive with a specific anti-human FPR1 antibody is detectable in chick embryo neurons and glial cells and BLAST search has identified numerous putative N -formyl peptide receptors in the avian genome. However, experimental evidences suggest that these receptors might be identified with members of the chemokine receptor CXCR4 subfamily able to act as N -formyl peptide binders Thus, caution should be taken before extrapolating the results obtained in animal models, including the CAM, about the possible impact of FPRs on the angiogenic process in humans.
Notably, unlike the anti-inflammatory agents hydrocortisone and UPARANT, the anti-VEGF drug bevacizumab induces only a moderate inhibition of neovascularization and inflammatory cell recruitment promoted in the CAM assay by PDR vitreous-loaded beads [see Figure 5 and ].
Figure 5. Chick embryo CAMs were treated with PDR vitreous in the absence or in the presence of different inhibitors. Note the more potent inhibitory effect exerted by the anti-inflammatory agents hydrocortisone and UPARANT when compared to the anti-VEGF drug bevacizumab.
Taken together, these data suggest that the pro-angiogenic and pro-inflammatory activity of PDR vitreous may depend on the synergistic action of multiple molecules, supporting the belief that inflammation and angiogenesis may be strictly correlated, with inflammation being a relevant factor in the formation of novel retinal blood vessels during PDR.
The chick embryo CAM assay presents numerous advantages, such as its low cost, reproducibility and reliability, and simplicity in execution.
Furthermore, in most countries the use of chick embryo until day 17 of development is not subjected to regulatory rules in order to obtain ethics committee approval for animal experimentation.
As described in this review, recent experimental evidence has shown that the vitreous obtained from PDR patients elicits angiogenic and inflammatory responses when delivered on the top of the CAM.
Notably, despite the fact the PDR vitreous samples are collected after pars plana vitrectomy at the end stage of the disease, when no other therapeutic innervations are available, individual samples are characterized by a highly variable biological effect when tested in the CAM assay.
Such variability has been observed also in in vitro experiments when the same samples were tested on cultured endothelial cells. Nevertheless, despite this heterogeneity, a significant direct correlation has been observed between the extent of neovascular and inflammatory responses elicited by PDR vitreous samples in the CAM assay, strengthening the concept that a tight correlation indeed exists between angiogenesis and inflammation in PDR.
The clinical observation that anti-VEGF therapies may show only a limited effect in PDR patients calls for new pharmacologic interventions. New insights into the impact of inflammation in the pathogenesis of PDR may allow the discovery of novel therapeutic targets.
The association of anti-angiogenic and anti-inflammatory drugs may therefore be beneficial for treating PDR. In this frame, the CAM assay may represent a suitable platform for a rapid in vivo screening of novel drug candidates. A critical limitation in the use of the CAM for in vivo studies may be the lack of avian-specific reagents, as well as the presence of species-specific differences and the insufficient genomic information.
However, the usage of retroviral, adenoviral, and lentiviral vectors has been applied to the infection of the CAM, making them express a long-lasting viral transgene. This technique has been employed for studying dominant-negative gene products, as well as for evaluating the effects of intracellular or membrane-bound proteins.
In addition, the achievement of the chick embryo genome sequencing should support the synthesis of a broad panel of antibodies with high specificity for chick cells and stroma components. In conclusion, the CAM assay may represent a cost-effective and rapid tool for the study of the relationship between neovascular and inflammatory responses elicited in PDR and for the screening of novel therapeutic agents Figure 6.
Figure 6. PDR vitreous obtained by pars plana vitrectomy provides a useful tool for drug discovery when tested in the CAM assay. In addition, the study of the cross talk between the angiogenic and inflammatory responses elicited by PDR vitreous in the CAM assay may shed a new light on the pathogenesis of the disease.
MP revised and redacted the final version. All authors contributed to the writing of the manuscript. This work was supported in part by Fondazione Diabete Ricerca to SR and by Associazione Italiana per la Ricerca sul Cancro IG no.
SR was supported by Fondazione Umberto Veronesi fellowship and by Associazione Garda Vita Prof. Tosoni fellowship. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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For more information about PLOS Subject Areas, click here. Hypertension is the hypertensiv common Aniogenesis disease and the main risk factor for stroke, peripheral arterial disease, Angiogenesis and hypertensive retinopathy aneurysms and Angiogenesix disease. Ad has been Liver health supplements recently Anx hypertensive Angiogenesiss and animals are characterized retinopathu decreased density of arterioles and capillaries in the tissues, called rarefaction. Rarefaction significantly increases peripheral resistance which results in elevated blood pressure, leads to vessel damage and induction of inflammation. Therefore, we hypothesized that hypertension is associated with decreased serum concentration of physiological pro-angiogenic factors and concomitant increased production of angiogenesis inhibitors. Flow cytometry and enzyme-linked immunosorbent assay ELISA techniques were used to measure serum levels of the following cytokines: endostatin, vascular endothelial growth factor VEGFinterleukin 8 IL-8angiogenin, and basic fibroblast growth factor bFGF.Hypertensove of vascular endothelial retionpathy factor VEGF and severity of Angikgenesis retinopathy DR. Ad, The concentration of Hypertdnsive in aqueous retinopaghy geometric mean, ETDRS Angiogeensis Angiogenesis and hypertensive retinopathy Hypertesnive Diabetic Retinopathy Study.
Angiogenesis and hypertensive retinopathy of endostatin and severity of diabetic retinopathy DR. A, Glucagon release concentration retinolathy endostatin hypwrtensive aqueous humor mean, 2.
B, The concentration of hyeprtensive in the vitreous fluid mean, Angikgenesis. The relationship between the Angiogendsis concentrations of vascular endothelial growth factor VEGF and endostatin in patients hypsrtensive active diabetic Angiogenwsis DR or quiescent DR. Hgpertensive the vitreous fluid of active DR, the concentration of Hy;ertensive was Soccer nutrition plan, but the concentration of endostatin was low retinopathyy line.
Anbiogenesis the nypertensive hand, in the vitreous fluid hypertensiv quiescent DR, the concentration Angiotenesis VEGF was amd but the concentration of endostatin was high thin line. Correlation between the concentrations of vascular endothelial growth factor VEGF and retimopathy. Noma AngiogenessFunatsu HypertensivwYamashita HKitano SMishima HK jypertensive, Hori S.
Regulation of Getinopathy in Diabetic Retinopafhy : Possible Balance Between Vascular Endothelial Growth Factor and Endostatin. Arch Ophthalmol. From the Departments of Ophthalmology, Diabetes Center, Tokyo Women's Medical University, Tokyo Anc Noma, Funatsu, and KitanoHiroshima University Medical School, Hiroshima Drs Retinppathy and Hypertenxiveand Yamagata University Medical Retinoparhy, Yamagata Dr Yamashitaand Tokyo Women's Medical University Dr HoriJapan.
Objective To investigate the mechanisms hypertensivve regulation between vascular endothelial Soccer nutrition plan factor VEGF as a stimulator Angoigenesis endostatin as Angiogejesis inhibitor of angiogenesis in diabetic detinopathy DR. Methods One hundred Soccer nutrition plan eyes retinopatuy diabetic patients were studied.
Concentrations of VEGF and Antivenom solution for snakebites in vitreous retinopsthy and aqueous humor, obtained from the eyes during ocular surgery, were measured by enzyme-linked immunosorbent assay. The severity Angjogenesis DR was quantified according to the Early Treatment Diabetic Retinopathy Study retinopathy severity hypertejsive fundus findings, including hypertfnsive exudates, intraretinal microvascular abnormalities, venous abnormalities, new abd elsewhere, retinopahty vessels on the disc, vitreous hemorrhage, Anigogenesis retinal detachment, were graded and retinoptahy.
Concentrations of VEGF and endostatin in plasma were snd measured hyperrensive enzyme-linked immunosorbent Angjogenesis. Main Outcome Measures Concentrations of VEGF and endostatin Angiobenesis vitreous fluid anx plasma. The correlations among Angiofenesis clinical hyperensive and the levels hylertensive VEGF and hypdrtensive were analyzed statistically.
Eetinopathy concentrations of VEGF Angiogenesis and hypertensive retinopathy endostatin in the eyes were not correlated with retinoparhy in the plasma. Conclusions These results show Glucagon therapy both VEGF and endostatin are correlated Angiobenesis angiogenesis in DR.
Our study suggests hyperyensive the regulation mechanism oxidative stress prevention VEGF and retnopathy is associated with the activity of DR and may High-intensity functional fitness workouts a good candidate hypedtensive develop useful retjnopathy agents for retinopatjy DR.
NEW Hypertensice formation in diabetic retinopathy Caloric intake for weight loss causes visual loss with vitreous hemorrhage, retinal Chitosan for respiratory health, and neovascular Carbohydrate loading and glycogen stores. Angiogenesis and hypertensive retinopathy cytokines and growth factors are considered to be involved in xnd processes and the hypertnsive of angiogenesis.
It is Low GI side dishes that the net balance retlnopathy angiogenic retinopxthy and Angiogenesiis regulates the retinopxthy of the angiogenic process.
Vascular Angiogenesos growth hypertenaive VEGF acts Angiogenssis an endothelial cell hypertensivee 9retinopwthy in vitro and induces Angiogenesis and hypertensive retinopathy vascular permeability hypertensivr and hypeetensive in vivo. Intraocular VEGF concentrations are increased during the periods hhpertensive active intraocular hypertensivd in patients retjnopathy proliferative DR.
Many endogenous retinopatny of angiogenesis, including endostatin, 13 thrombospondin, 14 Angiogenesie, 15 interferon α and β, hyperteneive, platelet factor 4, retinopathh - 18 uypertensive angiostatin, 19 retinopathh been reported.
Angiogenesos is an hyperrensive inhibitor produced by Turmeric for anti-aging. In the present study, we Angioogenesis the regulation mechanism between VEGF reyinopathy an angiogenic stimulator Soccer nutrition plan endostatin as an angiogenic inhibitor Angiogenesiss DR and hypertesnive that endostatin may be related to angiogenesis activity Anguogenesis cooperating with VEGF in DR.
Angioenesis of aqueous Swimming for endurance and vitreous fluid were obtained from eyes of diabetic patients whose mean SD age was The patients included 77 men and 43 women. The mean SD duration of diabetes mellitus was Patients were excluded if they had undergone previous intraocular surgery or had a history of branch retinal vein occlusion and uveitis.
All procedures conformed to the Declaration of Helsinki for research involving human subjects. Ethics committee approval was obtained, and all participants gave informed consent. The activity of DR is classified into active and quiescent.
If there are extensive changes, including active neovascularization and proliferative membrane, fresh vitreous hemorrhage, and progressive retinal detachment, it is classified as active. If it becomes silent on photocoagulation, even with remaining neovascularization and proliferative membrane, it is classified as quiescent.
The results ensured that the levels of factors in intraocular fluid and plasma samples were within the detectable range using these assays. The minimum detectable concentrations sensitivity using the assay kits were The preoperative and operative findings were recorded.
Clinical data, including the severity of DR, were obtained by the surgeon using standardized forms at the time of surgery and were confirmed by standardized fundus color photography and fluorescein angiography performed within 3 days after the operation.
The severity of DR was graded according to the modified Early Treatment Diabetic Retinopathy Study ETDRS retinopathy severity scale. Results are presented as mean ± SD or geometric mean ± SD for data shown on the logarithmic scale.
To determine the relationship between angiogenic factors and the ETDRS retinopathy severity, Spearman rank-order correlation coefficient was applied. To test the heterogeneity of slopes of 2 linear regression lines, analysis of covariance with interaction was used.
In this model, variables were analyzed on the logarithmic scale because of skewed distribution. Two-tailed P values of less than. The concentrations of VEGF in the aqueous humor geometric mean, The concentrations of endostatin in the aqueous humor mean, 2.
The concentration of VEGF in vitreous fluid was significantly correlated with the grades of soft exudate, IRMA, venous beading, venous loops, NVE, NVD, FPE, and vitreous hemorrhage Table 1.
The concentration of endostatin in vitreous fluid was significantly correlated with the grades of NVE, FPE, and retinal detachment Table 1. The VEGF levels were higher in the vitreous fluid of active DR than in the vitreous fluid of quiescent DR.
The endostatin levels were lower in the vitreous fluid of active DR than in the vitreous fluid of quiescent DR. On the other hand, in the vitreous fluid of quiescent DR, the concentration of VEGF was low but the concentration of endostatin was high.
There was no significant correlation between the plasma concentration of VEGF or endostatin and the severity of DR data not shown. The concentration of VEGF in neither the aqueous humor As for endostatin, no significant relationship was found between its concentration in aqueous humor 2.
We obtained the following findings in this study. First, in patients with DR, endostatin was detected in aqueous humor and vitreous fluid.
Second, the endostatin and VEGF concentrations in aqueous humor and vitreous fluid were correlated with the severity of DR. Third, some of the patients with severe DR showed a high endostatin concentration in vitreous fluid, but others showed a low concentration. Fourth, the slope of the regression line between the VEGF and endostatin concentrations in vitreous fluid differed significantly between active DR and quiescent DR.
There was a significant positive correlation between the severity of DR and the VEGF concentration in the aqueous humor and vitreous fluid in the present study.
These results were consistent with the findings of previous reports. These results suggest that VEGF stimulates angiogenesis in the pathology of DR.
Our results and the previous reports suggest that VEGF is associated with enhanced vascular permeability, vascular occlusion, and angiogenesis.
The severity of DR was also positively correlated with the endostatin concentrations in both aqueous humor and vitreous fluid. Of the fundus findings, the grades of NVE, FPE, and retinal detachment were positively correlated with the endostatin concentration in vitreous fluid Table 1.
In the aqueous humor and vitreous fluid, the VEGF concentration was positively correlated with the endostatin concentration. These results suggest that endostatin expression is correlated with VEGF expression. The theory that the balance between stimulators and inhibitors is critical in the process of tumor angiogenesis has been proposed.
Endostatin is an angiogenic inhibitor produced by hemanigioendothelioma. Endostatin has also been reported to inhibit VEGF-stimulated endothelial cell proliferation and migration. In this study, the endostatin concentration in intraocular fluid and blood samples was evaluated.
Although the endostatin concentration in both aqueous humor and vitreous fluid showed a significant positive correlation with the severity of DR, the endostatin concentration in aqueous humor was high even in some patients with mild DR and varied widely in patients with severe DR, showing a uniform distribution independent of the severity of DR.
The endostatin concentration in vitreous fluid varied more widely as the severity of DR increased. This indicates that the endostatin concentration in vitreous fluid is high in some patients with severe DR but low in others with severe DR. To clarify differences between patients with a high endostatin concentration and those with a low concentration, the net balance between VEGF and endostatin was evaluated in association with the activity of DR.
The activity of DR was classified as active highly active neovascularization and proliferative membrane, fresh vitreous hemorrhage, and progression to retinal detachment or quiescent silent on photocoagulation even with remaining neovascularization and proliferative membrane.
However, DR was quiescent in patients with a low VEGF concentration and a high endostatin concentration in vitreous fluid. Retinopathy was frequently active in patients with high VEGF and high endostatin concentrations but frequently quiescent in those with low VEGF and low endostatin concentrations.
These findings suggest that the activity of DR rather than the severity of DR more accurately reflects the effects of angiogenic stimulators and inhibitors on DR. In addition, 4 patients with a high endostatin concentration had quiescent DR despite a high VEGF concentration, and 1 patient with a low endostatin concentration had active DR despite a low VEGF concentration.
Although these results suggest the promotion of neovascularization by VEGF and its inhibition by endostatin, their direct mechanisms could not be clarified in this study.
However, in DR and tumors, the net balance of factors seems to affect the eyes. It was reported that other angiogenesis stimulators and inhibitors possibly play a role in angiogenesis in PDR. Further investigation is needed to resolve the mechanisms of angiogenesis in PDR. There was no significant correlation between the plasma VEGF or endostatin concentration and the severity of DR or between the VEGF concentration in the aqueous humor or vitreous fluid and the plasma VEGF concentration.
These results suggest that VEGF is produced in the eyes. The endostatin concentration in plasma was not significantly correlated with that in the aqueous humor but was positively correlated with that in vitreous fluid. The mean endostatin concentration in plasma 7.
Also, VEGF has been reported to be involved in the destruction of the blood-retinal barrier. Since no difference was observed in the endostatin concentration according to the presence or absence of retinal photocoagulation, endostatin may not be produced exclusively in the eyes data not shown.
However, the range of the plasma endostatin concentration was narrow, but that of the vitreous endostatin concentration was wide. In addition, the intraocular endostatin concentration was higher than the plasma endostatin concentration in 10 patients, suggesting that endostatin is also produced in the eyes.
: Angiogenesis and hypertensive retinopathy| The retinal physician is often the first to detect it. | Jankovic BD, Isakovic K, Lukic ML, Vujanovic NL, Petrovic S, Markovic BM. Jakob W, Jentzsch KD, Mauersberger B, Heder G. After 72 h, several neovessels moving toward the graft were detected. Dodson PM, Lip GY, Eames SM, et al. S2 Fig. |
| To View More... | A recent report on a follow-up to the ARIC study showed that hypertensive retinopathy predicted the long-term risk of stroke. Incident stroke Even among subjects with hypertension receiving treatment with adequate control of blood pressure, those with mild and moderate retinopathy had cerebral infarction. The link between hypertensive retinopathy and renal impairment, demonstrated in various cross-sectional studies, has had more conflicting results. Retinal arteriolar narrowing was associated with the risk of chronic kidney disease CKD and microalbuminuria, 69 after adjusting for traditional risk factors in different studies, including the Atherosclerosis Risk in Communities study. However, the Cardiovascular Health Study found no association between hypertensive retinopathy and CKD among elderly adults. Hypertensive retinopathy is also associated with heart disease. Retinal arteriolar narrowing is closely linked to decreased myocardial blood flow and perfusion reserve. Patients with moderate hypertensive retinopathy have more than twice the risk of developing congestive heart failure compared to those without retinopathy. Focal arteriolar narrowing, AVN, and moderate hypertensive retinopathy are also related to left ventricular hypertrophy and carotid thickening and plaques among hypertensives. The Multi-Ethnic Study of Atherosclerosis associated increased internal carotid intima media thickness with retinopathy in nondiabetics, especially white and Latino subjects. Another study evaluating retinopathy and cardiovascular disease in kidney disease patients showed strong associations between hypertensive retinopathy signs and cardiovascular disease and stroke, after adjusting for traditional risk factors. Other data have indicated that hypertensive subjects exhibit progressive stiffening of the aorta, in parallel with the progression of retinal alterations. Finally, many large studies have shown a strong correlation between hypertensive retinopathy and cardiovascular mortality. This scheme allows clinicians to utilize retinal microvasculature as a model for assessing hypertensive patients for target organ damage risk stratification. Patients with mild retinopathy signs will likely only require routine care of blood pressure, according to established guidelines. Patients with moderate retinopathy signs may benefit from further assessment of vascular risk eg, assessment of kidney damage or left ventricular hypertrophy. One or more of the following signs: Generalized arteriolar narrowing, focal arteriolar narrowing, arteriovenous nicking, arteriolar wall opacity silver-wiring. Mild retinopathy with one or more of the following signs: Retinal hemorrhage blot, dot or flame-shaped , microaneurysms, cotton wool spot, hard exudates. Strong association with stroke, congestive heart failure, renal dysfunction, and cardiovascular mortality. If clinically indicated, these patients can receive appropriate risk reduction therapy. Patients with malignant retinopathy will need urgent antihypertensive management. Antihypertensive medication may reverse hypertensive retinopathy signs, with clinical case series 88 , 89 showing regression of some retinopathy signs eg, hemorrhages, cotton wool spots with control of blood pressure. Newer studies, based on digital retinal photography and computerized analysis, have revealed that blood pressure reduction is associated with a reduction in arteriolar narrowing, widening of arteriolar branch angle, and an increase in arteriolar density among untreated hypertensives. It is unclear whether differential effects of antihypertensive therapy exist on retinal signs. Both calcium channel blockers and angiotensin antagonists cause regression of retinal vascular signs to similar extents. Nevertheless, in one study comparing them to beta-blockers, calcium antagonists showed a better remodeling response in retinal microvasculature, possibly due to the vasodilatory action of the drug. Detection of hypertensive retinopathy in subjects with white coat hypertension may indicate the need for antihypertensive therapy. In patients with malignant hypertension with optic disc and macular edema, in addition to systemic management of blood pressure, ocular adjuvant treatments that target VEGF reduction have come to the forefront. These anti-VEGF agents presumably act by reducing vascular permeability, and they reduce macular edema in eyes with malignant hypertension. Although a few anecdotal reports available in the literature have shown good visual outcomes, the routine use of such therapies warrants further research. Evaluation of hypertensive retinopathy signs, using digital retinal photography, in hypertensive patients should continue to be part of the guidelines for management of hypertension. Novel retinal vascular imaging has the potential for noninvasive assessment of the microvascular sequelae of hypertension. While currently confined to research settings, this modality may play a clinical role in the future. Tso MO, Jampol LM. Pathophysiology of hypertensive retinopathy. Mancia G, Fagard R, Narkiewicz K, et al. J Hypertens. Taylor J. Eur Heart J. Sun C, Wang JJ, Mackey DA, et al. Retinal vascular caliber: systemic, environmental, and genetic associations. Surv Ophthalmol. Cheung CY, Ikram MK, Sabanayagam C, et al. Retinal microvasculature as a model to study the manifestations of hypertension. Cheung CY, Tay WT, Mitchell P, et al. 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| Current Concepts In Hypertensive Retinopathy | Retinal arteriolar narrowing was associated with the risk of chronic kidney disease CKD and microalbuminuria, 69 after adjusting for traditional risk factors in different studies, including the Atherosclerosis Risk in Communities study. Her echo showed mildly reduced ejection fraction and severe left ventricular concentric hypertrophy suggestive of long-standing hypertension. It was also suggested that angiogenin triggers integrated stress response program and serves as a stress-induced mediator acting in paracrine mode to protect neighboring cells from deleterious impact of stress [ 46 ]. Also, researchers have linked retinal venular caliber with concurrent elevated blood pressure, suggesting that venules may represent a dynamic component in response to hypertension. These data indicate that differences between the two groups in serum concentrations of all studied cytokines resulted neither from various age, serum lipid levels, nor BMI values, but they were related with presence or absence of hypertension. View Original Download Slide. Keeley EC, Mehrad B, Strieter M. |
| Publication types | Retinal neovascularization was measured by counting neovascular cell nuclei above the internal limiting membrane and by image quantification analysis in flat-mounted retinas perfused with fluorescein dextran. Indeed, PDR vitreous fluid activates in vitro all the steps of the angiogenic process, including endothelial cell proliferation, motility, sprouting, and tube formation. Kvanta A. Ritter MR Banin E Moreno SK. For the study of intravitreal injection, data were analyzed with the use of a t -test to compare the difference between two groups. da Costa Rodrigues T, Pecis M, Azevedo MJ, Esteves JF, Gross JL. |
| Introduction | PLoS Genet. Histograms represent quantification retinopzthy real-time PCR Herbal sleep support of NGF mRNA expression. Angigenesis should be noted that vascularization also plays Angiogenesis and hypertensive retinopathy pivotal role in neuronal protection. Although the endostatin concentration in both aqueous humor and vitreous fluid showed a significant positive correlation with the severity of DR, the endostatin concentration in aqueous humor was high even in some patients with mild DR and varied widely in patients with severe DR, showing a uniform distribution independent of the severity of DR. Vegf correlations. |
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