Abnormal Blood Vessel Growth Research Articles

Targeting Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2): Latest Insights on Synthetic Strategies

Vascular endothelial growth factor receptor 2 (VEGFR-2) is a crucial mediator of angiogenesis, playing a pivotal role in both normal physiological processes and cancer progression. Tumors harness VEGFR-2 signaling to promote abnormal blood vessel growth, which is a key step in the metastasis process, making it a valuable target for anticancer drug development. While there are VEGFR-2 inhibitors approved for therapeutic use, they face challenges like drug resistance, off-target effects, and adverse side effects, limiting their effectiveness. The quest for new drug candidates with VEGFR-2 inhibitory activity often starts with the selection of key structural motifs present in molecules currently used in clinical practice, expanding the chemical space by generating novel derivatives bearing one or more of these moieties. This review provides an overview of recent advances in the development of novel VEGFR-2 inhibitors, focusing on the synthesis of new drug candidates with promising antiproliferative and VEGFR-2 inhibition activities, organizing them by relevant structural features.

The perspective of ceRNA regulation of circadian rhythm on choroidal neovascularization

Abnormal growth of blood vessels (choroidal neovascularization) can lead to age-related macular degeneration (AMD) and eventually cause vision loss due to detachment of the retinal pigmented epithelium. This indicates that choroidal neovascularization is important for the treatment of AMD. The circadian clock in the mammalian retina is responsible for controlling various functions of the retina, enabling it to adjust to changes in light and darkness. Recent studies have revealed a potential connection between the circadian clock and eye diseases, although a cause-and-effect relationship has not been definitively established. C57BL/6J male mice (aged 6 weeks) were randomly divided into two groups (Control group: 9:00–21:00 light period (300 lx); Jet lag group: 8-hour phase advance once every 4 days). A laser-induced CNV model was created after 2 weeks of feeding in a controlled or jet-lagged environment. Then, full transcriptome sequencing was performed. The pathways regulated by differentially expressed mRNAs were identified by GO analysis and GSEA. Further protein networks were constructed with the STRING database and Cytoscape software. WGCNA was used to further explore the co-expression modules of these differential genes and the correlation between these differential genes and phenotypes. ceRNA networks were constructed with miRanda and TargetScan. The pathways associated with the overlapping differentially expressed mRNAs in the ceRNA network were identified, and the hub genes were validated by qPCR. A total of 661 important DEGs, 31 differentially expressed miRNAs, 106 differentially expressed lncRNAs and 87 differentially expressed circRNAs were identified. GO and GSEA showed that the upregulated DEGs were mainly involved in reproductive structure development and reproductive system development. The STRING database and Cytoscape were used to determine the protein interaction relationships of these DEGs. WGCNA divided the expression of these genes into several modules and screened the hub genes of each module separately. Furthermore, a ceRNA network was constructed. GO analysis and GSEA showed that these target DEmRNAs mainly function in wound healing, cell spreading, epiboly involved in wound healing, epiboly, and morphogenesis of an epithelial sheet. Finally, ten key genes were identified, and their expression patterns were confirmed by real-time qPCR. In this study, we investigated the regulatory mechanism of ceRNAs in choroidal neovascularization according to different light-dark cycles in the eyeball.

Targeting the VEGFR2 signaling pathway for angiogenesis and fibrosis regulation in neovascular age-related macular degeneration

Neovascular age-related macular degeneration (nAMD) is characterized by abnormal blood vessel growth from the choroid, leading to complications and eventual blindness. Despite anti-VEGF therapy, subretinal fibrosis remains a major concern, as VEGF/VEGF receptor-2 (VEGFR2) signaling can contribute to both angiogenesis and fibrosis. For the identification of the aqueous humor proteome, we performed liquid chromatography with tandem mass spectrometry analysis. To investigate the potential therapeutic effects of targeting the VEGF signaling pathway using apatinib, a highly selective VEGFR2 tyrosine kinase inhibitor, this study employed in vitro (THP-1 conditioned media-treated ARPE-19 cells) and in vivo (laser-induced choroidal neovascularization mouse) models of nAMD. This study revealed elevated VEGFR2 protein levels in the aqueous humor of nAMD patients, suggesting a potential target to mitigate neovascularization and fibrosis in nAMD. Apatinib effectively reduced VEGFA and αSMA levels in both in vitro and in vivo models. Moreover, apatinib showed improvement in laser-induced subretinal hyper-reflective lesions. The action mechanism was linked to the inhibition of VEGFR2 activation, leading to the suppression of both angiogenesis and fibrosis through the downregulation of STAT3 phosphorylation. Therefore, the VEGFR2 signaling pathway appears to play a central role in the development of nAMD by regulating both angiogenesis and fibrosis.

Cationic amphiphilic molecules as novel sclerosants for venous malformation treatment: A study on tranexamic acid-derived low-molecular-weight gels

Venous malformation (VM) is a prevalent congenital vascular anomaly characterized by abnormal blood vessel growth, leading to disfigurement and dysfunction. Sclerotherapy, a minimally invasive approach, has become a primary therapeutic modality for VM, but its efficacy is hampered by the rapid dilution and potential adverse effects. In this study, we introduced a series of cationic amphiphilic molecules, fatty alcohol esters (TA6, TA8, and TA9) of tranexamic acid (TA), which self-assembled into low-molecular-weight gels (LMWGs) in water. The TA9, in particular, is released slowly when hydrogel is injected into the vein locally. Then, it damages the venous wall by destroying cell membranes and precipitating proteins, causing inflammation and thrombosis, thickening of the venous wall, effectively inducing irreversible vein fibrosis. Additionally, TA9 can be rapidly degraded into TA in plasma to reduce toxicity caused by diffusion. Overall, this study suggests that the cationic amphiphilic molecule TA9 is a promising sclerosant for VM treatment, offering a novel, effective, and safe therapeutic option with potential for clinical translation.

Endothelial c-Src mediates neovascular tuft formation in Oxygen-Induced Retinopathy

Vascular retinopathy, characterised by abnormal blood vessel growth in the retina, frequently results in vision impairment or loss. Neovascular tufts, a distinctive pathological feature of this condition, are highly leaky blood vessel structures, exacerbating secondary complications. Despite their clinical significance, the mechanisms underlying tuft development are not fully elucidated, posing challenges for effective management and treatment of vascular retinopathy. This study investigates the role of c-Src in neovascular tuft formation. Although c-Src has been acknowledged as a pivotal regulator in developmental angiogenesis within the retinal vasculature, its specific role in governing pathological retinal angiogenesis remains to be fully understood.The Oxygen-Induced Retinopathy (OIR) model was used for neovascular tufts formation in both Cre-mediated vascular specific c-Src knockout mice and wildtype littermates. High-resolution imaging and analysis of isolated retinas was conducted. c-Src depletion demonstrated a significant reduction in neovascular tufts within the OIR model. This decrease in tuft formation was observed independently of any alterations in cell death, cell proliferation or cell adhesion and the absence of c-Src did not impact tuft pericyte coverage and junctional morphology. These findings underscore the critical role of c-Src in the pathogenesis of neovascular tufts in vascular retinopathy. Understanding the molecular mechanisms involving c-Src may offer valuable insights for the development of targeted therapies aimed at mitigating vision-threatening complications associated with retinopathy.

Risk factors for the time to development of retinopathy of prematurity in premature infants in Iran: a machine learning approach

BackgroundRetinopathy of prematurity (ROP), is a preventable leading cause of blindness in infants and is a condition in which the immature retina experiences abnormal blood vessel growth. The development of ROP is multifactorial; nevertheless, the risk factors are controversial. This study aimed to identify risk factors of time to development of ROP in Iran.MethodsThis historical cohort study utilized data from the hospital records of all newborns referred to the ROP department of Farabi Hospital (from 2017 to 2021) and the NICU records of infants referred from Mahdieh Hospital to Farabi Hospital. Preterm infants with birth weight (BW) ≤ 2000 g or gestational age (GA) < 34 wk, as well as selected infants with an unstable clinical course, as determined by their pediatricians or neonatologists, with BW > 2000 g or GA ≥ 34 wk. The outcome variable was the time to development of ROP (in weeks). Random survival forest was used to analyze the data.ResultsA total of 338 cases, including 676 eyes, were evaluated. The mean GA and BW of the study group were 31.59 ± 2.39 weeks and 1656.72 ± 453.80 g, respectively. According to the criteria of minimal depth and variable importance, the most significant predictors of the time to development of ROP were duration of ventilation, GA, duration of oxygen supplementation, bilirubin levels, duration of antibiotic administration, duration of Total Parenteral Nutrition (TPN), mother age, birth order, number of surfactant administration, and on time screening. The concordance index for predicting survival of the fitted model was 0.878.ConclusionOur findings indicated that the duration of ventilation, GA, duration of oxygen supplementation, bilirubin levels, duration of antibiotic administration, duration of TPN, mother age, birth order, number of surfactant administrations, and on time screening are potential risk factors of prognosis of ROP. The associations between identified risk factors were mostly nonlinear. Therefore, it is recommended to consider the nature of these relationships in managing treatment and designing early interventions.

Reviewing hemangiomas and vascular malformations: An in-depth analysis

This narrative review delves into the intricacies of hemangiomas and vascular malformations (VMs), exploring their characteristics, diagnostic approaches, and therapeutic interventions. Hemangiomas, characterized by an abnormal growth of blood vessels, and VMs, arising from developmental abnormalities in blood vessels, present multifaceted challenges in clinical practice. The review navigates through the clinical manifestations and classifications of these vascular anomalies, emphasizing the importance of accurate diagnosis based on clinical evaluation, imaging techniques, and histopathological assessment. Variations in presentation, ranging from asymptomatic lesions to severe complications impacting vital organs, underscore the necessity for comprehensive understanding and tailored management strategies. Moreover, this review examines current therapeutic modalities encompassing medical, interventional, and surgical interventions. It synthesizes the evolving landscape of treatment options and highlighting the benefits, limitations, and potential adverse effects associated with each approach. In addition, the review underscores the significance of a multidisciplinary approach, integrating expertise from dermatology, radiology, and surgery, to optimize patient care and outcomes. The challenges posed by these vascular anomalies necessitate ongoing research endeavors aimed at refining diagnostic criteria and advancing therapeutic innovations. This review amalgamates existing knowledge and providing clinicians and researchers with a comprehensive understanding of hemangiomas and VMs, thereby fostering continued exploration and innovation in this complex field.

Comparative Analysis of Diabetic Retinopathy Using Deep Learning Concepts

Diabetic retinopathy is a complication of diabetes that affects the eyes. It is a progressive disease that occurs in stages, each of which is characterized by specific changes in the retina. It is caused by damage to the blood vessels in the retina, which is the light-sensitive part of the eye that sends visual signals to the brain. People with diabetes, especially those with poorly controlled blood sugar levels, are at risk of developing diabetic retinopathy. Over time, high blood sugar levels can cause the blood vessels in the retina to become damaged or blocked. This can lead to swelling, bleeding, and the growth of abnormal blood vessels in the retina, which can cause vision loss or even blindness. Symptoms of diabetic retinopathy may include blurry vision, floaters (spots in the field of vision), and difficulty seeing at night. However, many people with diabetic retinopathy may not have any symptoms at all in the early stages of the condition. Treatment for diabetic retinopathy may involve controlling blood sugar levels, blood pressure, and cholesterol levels, as well as laser treatment, injections, or surgery in more advanced cases. Regular eye exams are also recommended for people with diabetes to detect any early signs of diabetic retinopathy and prevent vision loss. Keywords: Diabetic Retinopathy; Deep Learning; Image processing; Convolution neural network

A Study on the Patients Effected with Diabetic Retinopathy

Diabetes-related retinal disease (DR) is the subject of the investigation. One of the main reasons why diabetic individuals become blind is diabetic retinopathy syndrome. DR is classified into two major types, first Non-Proliferative Diabetic Retinopathy (NPDR) and the second Proliferative Diabetic Retinopathy (PDR). The treatment can be given to the patients based on the neovascularization (Abnormal Blood Vessel Growth) in the retina. Early findings of neovascularization are much important. Based on this report only an optometrist can identify, whether if the patient comes under NPDR or PDR. NPDR is further classified into three stages, Mild NPDR, Moderate NPDR and Severe NPDR. The main causes of vision impairment in this group of patients are of concern. Early diagnosis, careful observation, and appropriate evidence-based management—which frequently involves several different health care disciplines and professions—are necessary for diabetes and diabetic retinopathy (DR). The one area of the body where physical damage to blood vessels brought on by systemic disorders can be seen noninvasively is treated and observed by an optometrist. This highlights how crucial it is to keep an eye on all diabetic patients and collaborate with endocrinologists or primary care physicians (PCPs) to properly manage these individuals. In the past, skilled professionals would treat patients by hand. However, with the rapid advancement of technology, diabetic retinopathy may now be treated digitally. A specialist can identify the more intricate characteristics of the eye and treat patients appropriately.

Photoreceptors inhibit pathological retinal angiogenesis through transcriptional regulation of Adam17 via c-Fos

Pathological retinal angiogenesis profoundly impacts visual function in vascular eye diseases, such as retinopathy of prematurity (ROP) in preterm infants and age-related macular degeneration in the elderly. While the involvement of photoreceptors in these diseases is recognized, the underlying mechanisms remain unclear. This study delved into the pivotal role of photoreceptors in regulating abnormal retinal blood vessel growth using an oxygen-induced retinopathy (OIR) mouse model through the c-Fos/A disintegrin and metalloprotease 17 (Adam17) axis. Our findings revealed a significant induction of c-Fos expression in rod photoreceptors, and c-Fos depletion in these cells inhibited pathological neovascularization and reduced blood vessel leakage in the OIR mouse model. Mechanistically, c-Fos directly regulated the transcription of Adam17 a shedding protease responsible for the production of bioactive molecules involved in inflammation, angiogenesis, and cell adhesion and migration. Furthermore, we demonstrated the therapeutic potential by using an adeno-associated virus carrying a rod photoreceptor-specific short hairpin RNA against c-fos which effectively mitigated abnormal retinal blood vessel overgrowth, restored retinal thickness, and improved electroretinographic (ERG) responses. In conclusion, this study highlights the significance of photoreceptor c-Fos in ROP pathology, offering a novel perspective for the treatment of this disease.

Effect of Nasal Continuous Positive Airway Pressure on Retinopathy of Prematurity in Preterm Newborns: A Comparative Analysis with Mechanical Ventilation and High-Flow Nasal Cannula Therapy.

BACKGROUND Retinopathy of prematurity (ROP), originally described as retrolental fibroplasia, represents an abnormal growth of blood vessels in the premature retina that can occur in response to oxygen therapy. The association between ROP and invasive mechanical ventilation has been widely studied in the literature; however, the relationships between different types of ventilation and ROP have not been as well documented. This study aimed to compare the association of ROP incidence with mechanical ventilation (MV), nasal continuous positive airway pressure (nCPAP), and high-flow nasal cannula (HFNC) therapies in 130 pre-term infants with gestational ages <32 weeks. MATERIAL AND METHODS The study includes 130 premature newborns, out of which 54 underwent MV therapy, either alone or in combination with nCPAP or HFNC therapy, 63 underwent nCPAP therapy, either alone or in combination with MV or HFNC therapy, and 23 underwent HFNC therapy, either alone or in combination with MV or nCPAP therapy. The relationships between ROP and the 3 types of ventilation were analyzed by univariate followed by multivariate logistic regression. RESULTS When adjusting for covariates, only nCPAP and birth weight were significantly associated with ROP, the former being a strong risk factor, with an adjusted odds ratio (AOR) of 7.264 (95% CI, 2.622-20.120; P<0.001), and the latter being a weak protective factor, with an AOR of 0.998 (95% CI, 0.996-0.999; P<0.05). CONCLUSIONS The results showed nCPAP was a strong ROP risk factor, birth weight was a weak ROP protective factor, and MV and HFNC were not significantly associated with increased ROP risk.

Cone cell dysfunction attenuates retinal neovascularization in oxygen-induced retinopathy mouse model.

Aberrant neovascularization is the most common feature in retinopathy of prematurity (ROP), which leads to the retinal detachment and visual defects in neonates with a low gestational age eventually. Understanding the regulation of inappropriate angiogenic signaling benefits individuals at-risk. Recently, neural activity originating from the specific neural activity has been considered to contribute to retinal angiogenesis. Here, we explored the impact of cone cell dysfunction on oxygen-induced retinopathy (OIR), a mouse model commonly employed to understand retinal diseases associated with abnormal blood vessel growth, using the Gnat2cpfl3 (cone photoreceptor function loss-3) strain of mice (regardless of the sex), which is known for its inherent cone cell dysfunction. We found that the retinal avascular area, hypoxic area, and neovascular area were significantly attenuated in Gnat2cpfl3 OIR mice compared to those in C57BL/6 OIR mice. Moreover, the HIF-1α/VEGF axis was also reduced in Gnat2cpfl3 OIR mice. Collectively, our results indicated that cone cell dysfunction, as observed in Gnat2cpfl3 OIR mice, leads to attenuated retinal neovascularization. This finding suggests that retinal neural activity may precede and potentially influence the onset of pathological neovascularization.

Nanoparticle‐based sustained drug delivery for the treatment of ocular neovascular diseases

Aims/Purpose: Nanoparticles have shown great potential as a drug delivery system for the treatment of neovascular ocular diseases characterized by the growth of abnormal blood vessels in the retina. The current standard of therapy for neovascular ocular diseases involves administering monoclonal antibody‐based anti‐VEGF drugs via intravitreal injections on a periodic basis. The short half‐lives of these drugs necessitate frequent injections, which can limit the effectiveness of the treatments. Hence, there is a need to develop new approaches for enhanced bioavailability and sustained and long‐lasting delivery of anti‐VEGF drugs. The aim of this study was to utilize poly (glycerol sebacate) (PGS) nanoparticles to achieve an extended release of anti‐VEGF (anti‐vascular endothelial growth factor) drugs, with the objective of reducing the frequency of intravitreal injections required for treatment.Methods: Double emulsion solvent evaporation method was utilized for the synthesis of PGS nanoparticles. Nanoparticle size and polydispersity index (PDI) were determined with dynamic light scattering method.Results: Nanoparticles were synthesized with a size of approximately 150 nm and PDI less than 0.3. The encapsulation efficiency of nanoparticles loaded with anti‐VEGF drugs was found to be 74%. The 30% drug release from nanoparticles in the first 2 months indicates that nanoparticles are a promising candidate for sustained drug release applications. Cell‐viability studies showed that anti‐VEGF drug‐loaded nanoparticles did not exhibit toxicity to ARPE‐19 cells, but they did exhibit anti‐angiogenesis properties by inhibiting the growth of HUVEC cells in a concentration‐dependent manner.Conclusions: The development of new‐generation materials for the storage and preservation of anti‐VEGF drugs, as well as their enhancement with prolonged release, will considerably improve the efficacy of long‐term treatment strategies for ocular neovascular diseases.

Cell and molecular targeted therapies for diabetic retinopathy.

Diabetic retinopathy (DR) stands as a prevalent complication in the eye resulting from diabetes mellitus, predominantly associated with high blood sugar levels and hypertension as individuals age. DR is a severe microvascular complication of both type I and type II diabetes mellitus and the leading cause of vision impairment. The critical approach to combatting and halting the advancement of DR lies in effectively managing blood glucose and blood pressure levels in diabetic patients; however, this is seldom achieved. Both human and animal studies have revealed the intricate nature of this condition involving various cell types and molecules. Aside from photocoagulation, the sole therapy targeting VEGF molecules in the retina to prevent abnormal blood vessel growth is intravitreal anti-VEGF therapy. However, a substantial portion of cases, approximately 30-40%, do not respond to this treatment. This review explores distinctive pathophysiological phenomena of DR and identifiable cell types and molecules that could be targeted to mitigate the chronic changes occurring in the retina due to diabetes mellitus. Addressing the significant research gap in this domain is imperative to broaden the treatment options available for managing DR effectively.

Preserving sight: Managing and preventing diabetic retinopathy

Abstract Preserving eyesight in the presence of diabetic retinopathy, a subtle complication of diabetes, requires a proactive and comprehensive approach. This condition, characterized by the gradual deterioration of the blood vessels in the retina, can quietly advance and pose a significant threat to vision. Effectively managing this issue involves careful control of blood glucose levels through medications, dietary choices, and physical activity. By preventing prolonged high blood sugar levels, the main culprit behind retinal damage, individuals can slow down the progression of diabetic retinopathy and minimize its impact on vision. Medical interventions, such as laser therapies and anti-vascular endothelial growth factor injections, offer targeted measures to address abnormal blood vessel growth and leakage. Regular eye assessments are crucial, providing early detection opportunities even in the absence of obvious symptoms and allowing for timely intervention before irreversible damage occurs. Prevention is equally important, emphasizing proactive measures to avoid diabetic retinopathy. Monitoring blood pressure and lipid levels, along with adopting a health-conscious lifestyle, strengthens cardiovascular health, indirectly protecting the fragile retinal blood vessels. By following diabetes management protocols, maintaining a balanced diet, engaging in regular physical activity, and avoiding tobacco use, individuals can significantly reduce their vulnerability to diabetic retinopathy. Combined with efforts to increase community awareness and educate about the importance of regular eye check-ups, this comprehensive approach empowers individuals to actively manage their eye health, ultimately preserving the precious gift of sight.

Intravenous 3K3A-Activated Protein C Inhibits Murine Ocular Inflammation and Suppresses Ocular Choroidal Neovascularization

Introduction: Choroidal neovascularization (CNV) is characterized by the growth of newly formed abnormal blood vessels from the choroid extending into the neurosensory retina, leading to vision loss. CNV is a common cause of visual impairment in neovascular age-related macular degeneration (nAMD) patients. Current treatments failed to stop the continuity of the neurodegenerative process. Despite the urgency, no neuroprotective agent has been found yet to treat AMD and other neurodegenerative ocular diseases. 3K3A-activated protein C (APC) is a cell-signaling analog of the endogenous blood serine protease APC. Preclinical studies showed that circulating plasma 3K3A-APC readily crosses the blood-brain barrier (BBB) and reaches neurons due to EPCR-dependent transport. In rodent models of stroke, brain injury, and neurodegenerative disorders, 3K3A-APC exerts neuroprotective, anti-inflammatory, and vasculoprotective activities. Due to its pleiotropic effects, 3K3A-APC has advanced to clinical trial stages for treating acute brain damage and chronic neurodegenerative diseases, which share similarities with retinal neurodegenerative disorders. Notably, the retina is part of the central nervous system (CNS), and the blood-retina barrier shares functional and structural similarities with the BBB. We previously demonstrated that intraocular administration of 3K3A-APC functions as a pleiotropic cytoprotective molecule within the retina, reducing ocular inflammation, suppressing CNV growth, and exhibiting promising therapeutic potential as a neuroprotective agent for treating ocular disorders. Intraocular administration is commonly utilized for delivering therapeutics to treat retinal conditions. However, safety concerns, the burden on the healthcare system, and patient comfort may indicate that systemic administration of 3K3A-APC is a beneficial alternative. Aim: To determine whether intravenously injecting 3K3A-APC into mice tails will cross the blood-retina barrier, induce anti-inflammatory activities in the retina, and suppress CNV. Methods: The efficacy of systemic administration of 3K3A-APC was evaluated using two C57BL/6J murine models: the LPS-induced ocular inflammation and the laser-induced CNV model. CNV was triggered by laser and ocular inflammation was triggered by intravitreal injection of lipopolysaccharide (LPS). Murine recombinant 3K3A-APC was administered systemically via tail injection. Fluorescein isothiocyanate (FITC)-dextran perfusion followed by retinal flatmount staining with anti-CD11b was used to assess inflammatory co-localization of cells to retinal vessels. FITC-dextran perfusion followed by retinal pigment epithelium (RPE)-choroid flatmount was used to assess CNV vascular penetration using 3D confocal imaging. Results: LPS injection triggered robust inflammatory cell infiltration in both the anterior and posterior chambers of the eyes. Systemic administration of 3K3A-APC (0.5 mg/kg, 1 and 4 hours post-LPS) significantly inhibited ocular inflammation. Immunostaining performed 24 hours post LPS revealed that 3K3A-APC reduced the number of CD11b+ monocyte and their extravasation into the retinal parenchyma (Figure). In the laser-induced CNV model, systemic administration of 0.2 mg/kg 3K3A-APC was applied one hour and four days post-laser. Evaluation of retinal specimens ten days post-laser showed that 3K3A-APC treatment significantly suppressed CNV growth, attenuated the abnormal growth of blood vessels from the choroid into the sensory retina, and decreased myeloid cell recruitment to the RPE-choroid area. Conclusion: Our study reveals that systemically administered 3K3A-APC effectively inhibits ocular inflammation and reduces CNV formation. Drawing insights from the neuroprotective activities of 3K3A-APC in the brain and CNS and recognizing the retina, particularly the macula, as an extension of the brain, we propose 3K3A-APC as a potential neuroprotective treatment for AMD and other neurodegenerative retinal pathologies. Given the established safety of systemic 3K3A-APC administration in phase 2 clinical trials for ischemic stroke, our findings support further exploring 3K3A-APC as a novel therapeutic approach in ophthalmology. Further research is warranted to elucidate fully the mechanisms underlying 3K3A-APC's beneficial effects on the retina.

Vascular Cell Adhesion Molecule-1 (VCAM-1) contributes to macular fibrosis in neovascular age-related macular degeneration through modulating macrophage functions

BackgroundNeovascular age-related macular degeneration (nAMD) is a major cause of blindness in the elderly. The disease is due to the growth of abnormal blood vessels into the macula, leading to the loss of central vision. Intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors (e.g., anti-VEGF) is the standard of care for nAMD. However, nearly 50% of patients do not respond or respond poorly to the therapy. More importantly, up to 70% of nAMD patients develop macular fibrosis after 10 years of anti-VEGF therapy. The underlying mechanism of nAMD-mediated macular fibrosis is unknown although inflammation is known to play an important role in the development of abnormal macular blood vessels and its progression to fibro-vascular membrane. In this study, we measured the intraocular levels of adhesion molecule VCAM-1, ICAM-1, CD44, CD62L, and CD62P in nAMD patients with and without macular fibrosis and investigated the link between the levels of adhesion molecule and clinical features (e.g., visual improvement, retinal thickness, etc.). We further investigated the effect of VCAM-1 in macrophage function in vitro and the development of subretinal fibrosis in vivo using a two-stage laser-induced protocol.ResultsThe aqueous levels of ICAM-1, VCAM-1, CD44, and CD62L were significantly higher in nAMD patients compared to cataract controls. The aqueous level of VCAM-1 (but not other adhesion molecules) was significantly higher in patients with macular fibrosis than those without and the level correlated positively with the retinal thickness. VCAM-1 was highly expressed at the lesion site in the mouse model of subretinal fibrosis. Blocking VCAM-1 or its receptor VLA-4 significantly prevented macrophage infiltration and reduced subretinal fibrosis in vivo. VCAM-1 induced macrophage migration and upregulated the expression of Arg-1, Mmp12 and Il6 but down-regulated the expression of iNOS and Il1b in macrophages.ConclusionsVCAM-1 may contribute to the development of macular fibrosis in nAMD patients by modulating macrophage functions, including migration and profibrotic polarization.

Intravitreal injectable hydrogel rods with long-acting bevacizumab delivery to the retina.

Retinal vascular diseases such as neovascular age-related macular degeneration (nAMD) are the leading cause of blindness worldwide. They can be treated with intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents by inhibiting VEGF which is a major agent of abnormal blood vessel growth. However, because of drug's short half-life, clinical treatment often requires monthly repeated intravitreal injections, causing treatment burden and undertreatment. Among various kinds of drug carriers, in situ forming hydrogels have been studied as potential intravitreal drug carriers for the high drug loading, easy injection, controlled drug release, and protection of encapsulated drugs from the environment. However, gelation time, crosslinking degree, and drug release patterns following injection of a liquid that will be subsequently gelled in situ are susceptible to be hindered by dilution of the hydrogel precursor solution with body fluids (e.g., blood or vitreous). Here, we report an injectable pre-crosslinked hydrogel rod to overcome the limitations of in situ forming hydrogels and to extend intravitreal half-life of anti-VEGF for reducing intraocular injection frequency. Hydrogel rods can be simply prepared using in situ forming hydrogels, and injectable using a designed rod injector. The adjustable crosslinking degree of hydrogel rods easily controlled bevacizumab release profiles in a sustained manner. Compared with in situ forming hydrogels, hydrogel rods effectively reduced initial burst release, and showed sustained release with long-term drug efficacy in vitro. From the 4-month in vivo pharmacokinetic analysis, following the intravitreal injection of hydrogel rods, the half-life of bevacizumab in the vitreous and retina was significantly extended, and drug elimination to aqueous humor was effectively reduced. Finally, intraocular stability, degradation, and inflammatory response of hydrogel rods were evaluated. We expect that the hydrogel rod can be a potential drug delivery system for the treatment of nAMD and other conditions that need long-term and local sustained drug administration. STATEMENT OF SIGNIFICANCE: Herein, we report an injectable pre-crosslinked hydrogel rod based on an in situ forming hydrogel to achieve intravitreal long-acting anti-VEGF delivery to reduce injection frequency and improve the long-term visual outcomes of patients with retinal vascular diseases. Hydrogel rods were readily prepared using removable molds and injected using customized injectors. Compared to the in situ forming hydrogel, hydrogel rods showed significantly reduced initial burst release, controllable release profiles for several months, physical stability, and a long-acting anti-angiogenic effect. Animal studies demonstrated that the hydrogel rods dramatically prolonged the intraocular drug half-life while significantly reducing drug elimination for up to four months. Moreover, the biodegradability and safety of the hydrogel rods suggest their suitability as an advanced intravitreal DDS for treating retinal vascular diseases.

Systemic Dendrimer-Peptide Therapies for Wet Age-Related Macular Degeneration.

Wet age-related macular degeneration (AMD) is an end-stage event in a complex pathogenesis of macular degeneration, involving the abnormal growth of blood vessels at the retinal pigment epithelium driven by vascular endothelial growth factor (VEGF). Current therapies seek to interrupt VEGF signaling to halt the progress of neovascularization, but a significant patient population is not responsive. New treatment modalities such as integrin-binding peptides (risuteganib/Luminate/ALG-1001) are being explored to address this clinical need but these treatments necessitate the use of intravitreal injections (IVT), which carries risks of complications and restricts its availability in less-developed countries. Successful systemic delivery of peptide-based therapeutics must overcome obstacles such as degradation by proteinases in circulation and off-target binding. In this work, we present a novel dendrimer-integrin-binding peptide (D-ALG) synthesized with a noncleavable, "clickable" linker. In vitro, D-ALG protected the peptide payload from enzymatic degradation for up to 1.5 h (~90% of the compound remained intact) in a high concentration of proteinase (2 mg/mL) whereas ~90% of free ALG-1001 was degraded in the same period. Further, dendrimer conjugation preserved the antiangiogenic activity of ALG-1001 in vitro with significant reductions in endothelial vessel network formation compared to untreated controls. In vivo, direct intravitreal injections of ALG-1001 and D-ALG produced reductions in the CNV lesion area but in systemically dosed animals, only D-ALG produced significant reductions of CNV lesion area at 14 days. Imaging data suggested that the difference in efficacy may be due to more D-ALG remaining in the target area than ALG-1001 after administration. The results presented here offer a clinically relevant route for peptide therapeutics by addressing the major obstacles that these therapies face in delivery.

Primary Cardiac Angiosarcoma: A Review.

Primary cardiac angiosarcoma is a rare and aggressive malignancy originating from the endothelial lining of cardiac blood vessels. This review covers various aspects of the disease, including its pathogenesis, clinical presentation, diagnosis, treatment, and prognosis. The primary characteristic of cardiac angiosarcoma is the rapid growth of abnormal blood vessels that invade the heart muscle, leading to the destruction of healthy tissue. Due to its infiltrative nature and early spread, diagnosing and treating cardiac angiosarcoma present significant challenges. Transesophageal echocardiography (TEE) plays a crucial role in diagnosing cardiac tumors such as angiosarcoma due to its high sensitivity. Additional imaging techniques such as computed tomography (CT) and cardiac magnetic resonance imaging (MRI) help assess tumor anatomy and identify metastases. Histopathological examination and immunohistochemistry are essential for confirming the diagnosis, as they reveal distinct histological features and specific endothelial markers associated with primary cardiac angiosarcoma. Targeted therapies directed at the angiogenic mechanisms and molecular abnormalities hold promise for improving treatment outcomes. Early detection of primary cardiac angiosarcoma remains challenging due to its rarity, and the prognosis is generally poor due to advanced disease at the time of diagnosis. The review emphasizes the importance of a multidisciplinary approach and collaboration among different specialties to optimize the diagnosis, treatment, and follow-up care of patients with primary cardiac angiosarcoma. The ultimate goal is to enhance diagnostic methods and therapeutic approaches by advancing knowledge and promoting further research into this aggressive malignancy.