Tissue-Specific Vascular Endothelial Signals and Vector Targeting, Part B: 69 (Advances in Genetics)

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Make sure to buy your groceries and daily needs Buy Now. Let us wish you a happy birthday! Date of Birth. Day 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Month January February March April May June July August September October November December Year Please fill in a complete birthday Enter a valid birthday. Thank You! The mentioned characteristics of retinal endothelia are preserved over interactions with other cells of the retina including neurons, glial cells, and pericytes, which together with the RPE provide the blood retinal barrier [ 25 ].

In ocular vasculopathies, the vessels become leaky, a result of increased stimuli from VEGF and other inflammatory mediators, which cause alterations of junctions in the retinal endothelium [ 26 ]. In the process of pathogenic neovascularization, endothelial sprouting is mediated by ECs as major players in the tip and stalk of the new vessels [ 27 ]. Tip ECs migrate to guide the new forming vessel, and stalk ECs proliferate and build the sprout.

Subsequently, the formation of lumen occurs, and after recruitment and placement of other vascular cell types—pericytes and smooth-muscle cells—the new vessel is formed [ 28 ]. In nAMD, accumulated debris, or drusen deposits, activate a molecular signaling flow with a consequence of new capillaries growth from the choroid towards the retina [ 29 ]. In PDR, the presence of toxic metabolites causes destabilized conditions in the retinal vasculature with subsequent oxygen limitation in the tissue in which hypoxia triggers neovascularization in the retina [ 30 ].

RNV is recognized as vessel sprouts beginning in the retinal capillaries, then invading into the vitreous and neural layers of the retina.


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CNV sprouts from the choroidal vessels, which invade the subretinal space. Macular degeneration is identified as an age-related disease, carrying a high risk of blindness in non-treated cases. According to severity, AMD has been categorized as early, intermediate and late, where late AMD additionally subdivides into dry and wet forms [ 1 ]. Dry AMD is recognized as geographic atrophy and non-neovascular forms, and neovascular or wet AMD is identified as neovascularization in the choroid [ 5 ].

Generally, diabetic retinopathy DR is fairly frequent among adult diabetic persons and in progressive conditions has been reported to damage the retina [ 34 ]. DR is described as microvascular malfunctions during diabetes, and is recognized in three forms: diabetic maculopathy, background retinopathy, and PDR [ 35 , 36 ].

PDR is accompanied with the formation of new leaky micro-vessels in the retina, prone to bleeding, which results in vitreous hemorrhage, fibrosis, and ultimately retinal detaching. While RNV and CNV initiate in different vascular networks and affect different layers in the retina, clinical treatment of both pathological angiogenesis has been similar [ 1 , 37 ].

More classically, both are addressed by laser photocoagulation, albeit with different clinical approaches using lower energy laser treatments and panretinal targeting to ablate the vasculature in RNV, while higher energy laser is used in CNV. Of relevance, corticosteroids have been used to control inflammation associated with both PDR and AMD, with clinical benefits on reducing vascularization. More recently, the introduction of anti-VEGF immunostrategies in the treatment of ophthalmic pathologies has been largely used to address a myriad of ocular angiogenic pathologies.

A common intervention for the treatment of PDR is photocoagulation, using a laser treatment of panretinal photocoagulation. The laser injection generates laser-scars at the retina with the goal of reducing neovascularization [ 38 ]. Despite the clinical effectiveness of photocoagulation in halting angiogenesis, these treatments can cause undesirable side effects, including pain during application for the patient, long-lasting retinal scarring, and the possibility of declined peripheral vision. In contrast, focal photocoagulation is applied to CNV membranes, which slows the progression of neovascularization and visual loss.

Nonetheless, laser treatment of nAMD has been associated with higher risk of visual loss after treatment in patients with subfoveal AMD and can result in disciform scaring of the choroid [ 39 ]. Such corticosteroids modulate inflammation-mediated neovascularization and have shown relative potency in ameliorating RNV and CNV. Nevertheless, the use of corticosteroids in ophthalmology has displayed clinical differences in efficacy, pharmacokinetics, and safety profiles, associated to each specific molecule administered as well as inter-patient variation to treatment.

Presently, corticosteroids as adjuvants in anti-VEGF therapies have been emerging as therapeutic options in neovascular ocular diseases [ 42 ]. Different therapeutic methods have been investigated in previous studies, which include anti-VEGF agents that prevent the action of VEGF for angiogenesis during hypoxia reviewed in [ 44 , 45 ]. It is noteworthy to add that pegaptanib is rarely used nowadays, bevacizumab an anti-VEGF human recombinant antibody approved in oncology is used as an off-label treatment in ophthalmology, while ranibizumab and aflibercept, a Fab antibody fragment and a VEGFR-IgG chimeric protein respectively, are approved for clinical use in PDR and nAMD.

Vascular-Targeting Agent

However, intravitreal injection of anti-VEGFs raises the risk of post-injection, as well as drug-associated, side effects. In addition, repeated long-term injections are necessary for the treatment of ocular neovascularization, which may lead to increased ocular and systemic complications, together with high economic burden [ 46 ].

Notably, in some patients, anti-VEGF treatment is not effective, which highlights differences between patients or even between ocular vascular pathologies. Bevacizumab is used as an off-label drug in treatment programs for nAMD [ 47 ]. Ranibizumab and bevacizumab have been reported to be effective against CNV, and later, together with pegaptanib, both have been documented to be effective against RNV [ 48 , 49 , 50 ]. An optimal response to anti-VEGF ocular therapy should include both resolution of excess interstitial fluids, including subretinal fluid and intraretinal fluid, resolution of retinal thickening, and improvement of more than five letters, subject to the maximum effect based on starting visual acuity [ 52 ].

However, some reports indicated that the efficiency of anti-VEGF therapeutics reduced after long-term treatments. For instance, intravitreal injection of bevacizumab on the third administration decreased to half of the first administration. This condition—tachyphylaxis—can cause the recurrence of neovascularization after treatment with antibodies against VEGF [ 53 ]. Hence, studies concentrated on finding new targets for the treatment of RNV and CNV are afflicted by the mentioned challenges, and novel focus on different ECs from their corresponding origin is paramount.

High levels of oxygen are consumed by the retina, one of the most metabolically active tissues in the human body [ 54 ].

The retinal and choroidal circulations are responsible for sustaining the high oxygen levels required by the retina. In that manner, the choroidal vasculature having high vascular density, nourishes the external layers of the retina, including RPE as well as photoreceptors Figure 1 , while the inner layers of the retina are sustained by the retinal vasculature. The abnormalities in retinal vasculature, hemorrhage, soft exudates, and thickening of the BM can lead to oxygen deficiency and hypoxia, thus initiating elevation in the expression of angiogenesis factors.

It has been reported that the mean oxygen tension is considerably lower in the lens and vitreous cavity of diabetic patients than non-diabetic individuals [ 55 ]. Also, the expression levels of hypoxia-mediated factors were higher in preretinal membranes of diabetic mice and rats in comparison with non-diabetic controls [ 56 , 57 , 58 ]. Thickening of BM, drusen formation, and reactive oxygen species, which collectively stabilize and raise the levels of HIFs—the key transcription activators of hypoxic-mediated angiogenesis signaling—are of particular importance in hypoxia-mediated AMD progression and CNV [ 62 , 63 ].

Regardless of the differences in etiology, hypoxia with subsequent neovascularization is the basic factor involved in the pathology of both PDR and nAMD [ 11 ]. In mammalian embryonic development, the role of HIFs is fundamental as their genetic deletion led to embryonic lethality in mice, and plays an essential role in the regulation of metabolism in humans [ 66 ]. The conserved transcriptional complex, HIF-1, is expressed in many species and all cell types.

The bHLH motif mediates the binding of HIF to DNA, the central PAS domain enables the heterodimerization of the subunits, and the C-terminal domains are responsible for recruitment of other transcriptional co-regulator proteins and activation of transcription [ 67 ]. As such, in hypoxia the dioxygenases become inactive and HIF pathway is initiated. In the nucleus, HIF transcription factors recognize NCGTG sequence on promoters of target genes, and through recruitment of transcriptional coactivators, initiate the survival of cells in hypoxic conditions Figure 2 [ 11 ], via upregulation of several genes including angiogenesis growth factors such as VEGF, EPO, and anaerobic metabolism glycolysis and lactate [ 12 ].

Decreased oxygen supply in retinal tissues results in activation of HIFs. Angiogenesis is a process in which new blood vessels are generated from pre-existing ones. This is a physiological process in biological systems and is orchestrated by stimulation of ECs to proliferate and migrate. In pathology, angiogenesis is associated with a myriad of diseases, and in many cases associated with ischemia and hypoxia.

In ophthalmic diseases, neovascularization often results in decreased vision, concomitantly with metabolic and cellular dysfunction of ECs. Animal models of angiogenesis have been employed in research. However, due to complexity, high cost, time consuming procedure, ethical issues linked to animal use, and priority for checking human specific responses, researchers have invested in developing alternative in vitro models [ 72 ]. EC culture models are advantageous for the study of hypoxic and angiogenic conditions as they allow control and to specifically manipulate external interfering factors, granting higher reproducibility in angiogenic studies [ 73 ].

Beyond reproducibility, in vitro experiments have the advantages of lower costs, shorter times, and specific control of the parameters due to fewer numbers of independent variables [ 73 , 74 ]. Additionally, in vitro cellular models can be employed to assess different combinations of experimental parameters, often not applicable in animal models, due to experimental variation and ethical restrictions [ 75 ]. The ECs utilized for in vitro models can be immortalized cell-lines or primary cells [ 76 , 77 ]. Primary cells show limited cell division numbers, usually become non-proliferating or senescent within a few population divisions, and also denote inter-isolate variations.

In comparison, immortalized cell-lines generally grow faster, for greater passage numbers, although they may exhibit altered growth features, display tumorigenic potential with chromosomal aberrations, and secretion or expression of many tissue-specific factors can be decreased [ 72 ]. Thus, primary cultures of ECs are preferable in neovascularization research since they more closely relate to the physiology, function and metabolic activity of their native counterparts.

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The first isolated ECs—human umbilical vein endothelial cells HUVEC [ 78 ]—are nowadays well characterized and widely utilized in in vitro models of angiogenesis. They have been employed in various studies due to availability of umbilical veins, the simple isolation protocol, and the high purity of the isolated cultures [ 79 ]. Hence, the use of HUVECs may not be truly illustrative for the investigation of the involvement of ECs in pathophysiological mechanisms originating from ocular blinding diseases [ 15 ]. In this regard, to clarify the exact mechanisms of pathologic conditions of eye angiogenesis it would be beneficial to study the functions of ECs derived from the tissues where the disorder arises, particularly when the purpose is to translate preclinical findings to clinical practice [ 80 ].

Isolation and culture of ECs has been performed from different sources and species, including microvascular or macrovascular endothelium from bovine, murine, and human vessels [ 81 ]. In ophthalmic research, retinal and choroidal microvascular endothelia are fundamental parts in the development and progression of RNV and CNV, yet the etiological mechanisms have not been fully understood.

Primary REC and CEC provide an appropriate model of vascular endothelium for investigations of the alterations of genes and proteins expression, as well as their responses to environmental stimuli that mimic the eye neovascularization milieu [ 82 ].