Infantile hemangiomas (IHs) can lead to significant complications during the proliferative phase, particularly in thick lesions that are not adequately controlled by topical timolol due to its limited skin penetration. Oral propranolol is effective but limited by systemic side effects and resistance. To overcome these challenges, we developed a novel barbed microneedle (MN) system for depth-specific dual-drug delivery. Bleomycin (BLM) is loaded in the needle tips for deep ablation, while timolol (TM) is incorporated in the base hydrogel for superficial vasoconstriction, enabling synergistic therapy (TM-BLM@MN). The barbed structure secured prolonged retention in vivo. In vitro, the TM-BLM@MN significantly inhibited hemangioma stem cell proliferation, migration, and tube formation. In vivo, treatment of TM-BLM@MN achieved a 1.93-fold greater reduction in tumor volume compared to controls and markedly suppressed pathological angiogenesis by histology. TM-BLM@MN as a minimally invasive platform demonstrates high efficacy for thick IH and holds strong potential for clinical translation and home-based therapy.

Pathological angiogenesis, such as that observed in wet age-related macular degeneration (AMD), is difficult to reproduce in vitro using human-relevant models. Although organ-on-chip (OoC) systems incorporating retinal pigment epithelium (RPE) and endothelial barriers have been reported, models integrating human retinal organoids with vascular networks remain limited. Here, we present a fully 3D-printed microfluidic platform for co-culture of human induced pluripotent stem cell (hiPSC)-derived retinal organoids containing intrinsic RPE regions with endothelial cells. The device, fabricated from flexible thermoplastic polyurethane (TPU) on a transparent polyvinyl chloride (PVC) substrate, supports three-dimensional co-culture within a fibrin-Matrigel matrix. In this system, endothelial cells formed organized vascular networks that localized around RPE-associated regions of retinal organoids without direct tissue invasion. Organoid-endothelial co-culture resulted in increased VEGF secretion, while exogenous VEGF further enhanced endothelial localization near RPE regions without affecting organoid growth. Functional assays using fluorescent dextran and rhodamine-labeled liposomal nanoparticles demonstrated spatially restricted and time-dependent transport along vascularized regions adjacent to the organoid interface. This retinal organoid-on-chip provides a simple and robust in vitro platform for studying retinal-vascular interactions and vascular-mediated transport processes.

Role of regulatory T cells in modulating corneal neovascularization in a murine model of diabetes.

Computational modeling of anti-VEGFA drug interactions with VEGF-A: Insights into therapeutic strategies for neovascular AMD.

Microglial HMOX1 drives retinal angiogenesis via modulation of endothelial STAT3 signaling.

The NLRP3 inflammasome inhibitor OLT1177 attenuates retinal neovascularization and microglial inflammation with neuroprotective effects.

Prime editing for ocular gene therapy and disease modeling: a narrative review of advances, delivery, and translational readiness.

Cardiovascular disease (CVD) is the leading cause of death for many cancer survivors, a phenomenon traditionally attributed to shared risk factors and cardiotoxic chemotherapies. Here, we hypothesized that cancer may also directly promote atherosclerosis. Propensity-matched analyses confirmed significantly elevated cardiovascular event rates amongst cancer patients, independent of comorbidities such as smoking. Atheroprone mice implanted with colorectal tumors demonstrated accelerated features of plaque vulnerability, driven by pathological angiogenesis and intraplaque hemorrhage. Mechanistically, tumor-secreted TNF-α induced the pro-angiogenic factor LRG1 across multiple murine models and human plaques. Therapeutic interventions targeting these pathways, including with FDA-approved cytokine inhibitors or tumor resection, prevented plaque destabilization in mice and reduced coronary revascularization rates in patients. Together, these findings suggest that cancer may causally promote CVD and unveil novel translational strategies for cancer survivors.

Atherosclerosis (AS) is a disease characterized by chronic vascular wall inflammation and lipid deposition. Although lipid-lowering drugs such as statins have significantly reduced cardiovascular event rates, "residual inflammatory risk" remains a key factor driving disease progression and plaque rupture. As a central regulator of the inflammatory response, the nuclear factor-κappaB (NF-κB) signaling network comprises both canonical pro-inflammatory pathways and functionally more complex non-canonical pathways. Increasing evidence in recent years indicates that abnormal and sustained activation of the non-canonical NF-κB signaling pathway plays a pivotal role in driving plaque rupture. This review first elaborates on the shift in AS strategies from "lipid-lowering" to "anti-inflammatory" approaches, followed by an in-depth analysis of the molecular activation mechanisms of the NF-κB signaling pathway and its distinctiveness in the AS pathological process, along with its epigenetic regulation. It emphasizes how this pathway drives pathological angiogenesis and regulates vascular smooth muscle cell (VSMC) phenotypic switching and macrophage function, thereby forming a vicious cycle that amplifies inflammation and structural damage, ultimately leading to acute cardiovascular events. Finally, we systematically summarize current progress and challenges in drug development targeting the NF-κB pathway (e.g., targeting key kinases like NIK and IKKα), aiming to provide theoretical foundations and future directions for novel therapeutic strategies to stabilize coronary plaques and prevent acute coronary syndromes.

Endometriosis (EM) is a chronic inflammatory gynecological disorder characterized by ectopic endometrial-like lesions, where aberrant angiogenesis is a hallmark driving lesion establishment and progression. However, the transcriptional mechanisms underlying pathological vascular remodeling in EM remain unclear. In this study, we identified E26 transformation-specific 1 (ETS1) as a key transcriptional regulator in EM pathogenesis through integrative analysis of bulk and single-cell transcriptomic datasets. Across three independent transcriptome datasets and two validation cohorts, ETS1 expression was consistently elevated in endometriosis lesions, particularly in ovarian endometrioma. Single-cell RNA sequencing further revealed that ETS1 was predominantly expressed in endothelial cells and dynamically upregulated along the endothelial differentiation trajectory. Functional enrichment and pseudotime analyses indicated that ETS1 + endothelial cells exhibited enhanced angiogenic activity and vascular remodeling potential. Mechanistically, ETS1 amplified VEGF signaling by upregulating VEGFR1 and VEGFR2, while macrophage-derived VEGFA acted as the principal upstream activator within the lesion microenvironment. Collectively, our findings delineate the VEGF-ETS1 axis as a central driver of pathological angiogenesis in endometriosis, positioning ETS1 as both a mechanistic hallmark and a promising therapeutic target for endometriosis.

Metabolic pathways involved in retinal angiogenesis: Molecular mechanisms and therapeutic targets.

Homocysteine and diabetic retinopathy.

Inhibition of pathological angiogenesis in oxygen-induced retinopathy by arginine depletion with ADI-PEG20.

Alpha-difluoromethylornithine suppresses angiogenesis via the FLI1-CLEC14A-VEGFC pathway in retinal endothelial cells.

A visualization of inhibitory effects on VEGF-mediated signaling pathway in proliferating endothelial cells in neonatal mouse retina.

The development of small-molecule tyrosine kinase inhibitors remains a high-priority strategy in modern oncology, particularly those targeting the Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) to disrupt pathological angiogenesis. This study utilized a dual-methodology approach to evaluate a novel series of five coumarin nucleoside conjugates (5a-5e) as potential anti-cancer agents. Initially, the compounds' drug-likeness was confirmed via ADMET prediction, which established favorable pharmacokinetic profiles. This was followed by an integrated MTT cytotoxicity screening against Oct1 (head and neck) and C33a (cervical) cancer cell lines, which identified compound 5d as the most potent cellular agent. The core of the investigation involved a comprehensive in silico analysis targeting the VEGFR-2 tyrosine kinase domain (TKD). Molecular docking revealed that all five compounds possess significantly superior predicted binding affinities compared to the native ligand, ATP (- 25.44kJ/mol). Critically, the primary cellular lead 5d (- 29.46kJ/mol) and the strongest binder 5e (- 31.30kJ/mol) both surpassed the affinity of the clinical benchmark, Sorafenib (- 28.80kJ/mol), confirming their high potential as competitive inhibitors. Further validation using Molecular Dynamics (MD) simulation and MMPBSA analysis demonstrated exceptional dynamic stability and thermodynamic preference for the TKD-ligand complexes, firmly supporting the predicted binding hypothesis. In conclusion, compounds 5d and 5e are validated lead candidates possessing favorable absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, direct cellular cytotoxicity, and a robust computationally modeled dual-action profile. Future research is urgently mandated to perform VEGFR-2-specific functional assays to definitively validate the predicted anti-angiogenic mechanism and conduct in-vivo studies to assess therapeutic efficacy.

Retinopathy of prematurity (ROP) remains a leading cause of childhood blindness worldwide, necessitating new therapeutic strategies. Current interventions targeting advanced disease stages often fail to prevent long-term visual impairment. This study investigates the potential of sodium butyrate (NaB), an orally administered short-chain fatty acid, in preclinical models of ROP. Using the oxygen-induced retinopathy (OIR) mouse model, we demonstrate that daily oral NaB supplementation significantly protects against pathological angiogenesis, impacting not only vascular but also neuronal and microglial pathology in the inner retina. Notably, NaB shows efficacy in early-phase ROP intervention, as evidenced by studies in postnatal day 9 (P9) OIR mice and a novel hyperglycemia-associated retinopathy (HAR) model that mimics the hyperglycemic conditions of many premature infants. These findings highlight NaB as a promising alternative or adjunct therapy to current anti-VEGF treatments, offering protection across multiple retinal cell types and stages of ROP development. The study underscores the need for further research to elucidate the specific mechanisms of NaB's action, paving the way for its potential clinical application in ROP management. This research marks the first exploration of butyrate as a preventative and therapeutic agent for ROP, setting the stage for additional preclinical evaluations and optimization.

Diabetic retinopathy (DR) is a serious sight-threatening complication that occurs due to constant hyperglycemia. It is the most common and leading cause of vision impairment worldwide. The development and progression of DR involve a complex network of genetic and environmental factors. Vascular inflammatory pathways, oxidative stress and epigenetic modifications have been linked to the development of diabetic mediated retinopathy. Candidate gene studies have implicated variants in genes involved in glucose metabolism such as (ALR2), vascular regulation (VEGF) are closely associated with DR susceptibility. Hyperglycemia triggers several factors such as polyol pathway, advanced glycation end-products (AGEs) formation, activation of protein kinase C (PKC), dysregulation of the renin-angiotensin system (RAS). These pathways collectively induce oxidative stress, inflammation, vascular dysfunction and pathological angiogenesis that further intensify microvascular lesions resulting in DR pathogenesis. Emerging therapeutic strategies present anti-VEGF agents, PKC inhibitors, and drugs modulating RAS system. In addition, targeted medicine based on genetic risk profiling and novel gene therapy approaches hold great promise in DR treatment. Further research integrating multi-omics data, gene-environment interactions, and precise translational studies are required for improving DR management and associated risk factor.

Purpose: To determine whether omega-3 supplementation can reduce malondialdehyde (MDA) levels, vascular endothelial growth factor (VEGF) expression, tumor necrosis factor-alpha (TNF-α) expression, and vascular tuft formation in oxygen-induced retinopathy (OIR) mouse models. Study Design: Controlled laboratory experimental study. Place and Duration of Study: Animal Laboratory Unit (ALU), Faculty of Medicine, Udayana University, from Methods: Thirty-six male Sprague Dawley rats, aged one week and weighing 10–12 g were included. Rats were exposed to 75 ± 5% oxygen from postnatal day 7 (P7) to P12 in a sealed oxygen chamber to induce vaso-obliteration. They were then returned to room air (20% oxygen) from P13 to P17 to allow hypoxia-driven pathological neovascularization. After that, rats were randomly assigned to either the treatment or control group. The treatment group received omega-3 fatty acids at a dose of 0.4 mg/g body weight, administered once daily via nasogastric tube from P13 to P17. Control animals did not receive supplementation and were maintained on standard laboratory diet.Retinas allocated for histological assessment were processed for immunohistochemical evaluation of VEGF, TNF-α, and vascular tuft formation. Results: There was a statistically significant reduction in MDA levels, VEGF expression and TNF-α in the treatment group receiving omega-3 supplementation. The number of vascular tufts was notably lower following omega-3 administration, implying its potential to inhibit pathological angiogenesis. Conclusion: Omega-3 unsaturated fatty acids exhibit antioxidant, anti-inflammatory, and anti-angiogenic properties that help suppress pathological neovascularization in oxygen-induced retinopathy (OIR).

Retinopathy of prematurity in active forms forms retinal detachment, sharply limiting visual functions leading to poor vision and blindness, the timely use of vascular endothelial growth factor inhibitors can increase the effectiveness of retinopathy of prematurity treatment. The effect on pathological angiogenesis in retinopathy of prematurity has no experience of widespread use and is an innovative method in ophthalmological practice.Purpose. To evaluate the effect of the angiogenesis inhibitor aflibercept on the neuro-cognitive functions of premature infants with retinopathy of prematurity.Material and methods. The prospective cohort study included 20 premature infants diagnosed with retinopathy of prematurity who were treated with the vascular endothelial growth factor inhibitor aflibercept between 2021 and 2022. The ophthalmological status and neuro-cognitive development of patients were assessed according to the Bailey III scale: cognitive, linguistic (receptive and expressive communication), motor (fine and large motor skills).Results. Hypermetropic refraction was detected in 16 out of 20 patients, and myopic refraction in 4 patients. According to the results of an electrophysiological study (visual evoked potentials), the average amplitude of the P100 component (PpAmp) was 17.5 ± 2.5. The children’s neuro-cognitive and motor skills did not lag behind chronological age. 80% of the subjects showed a slight lag in language skills.Conclusions. The study shows a moderate decrease in the development of the visual analyzer in children with retinopathy of prematurity. The results of the work showed the absence of toxic effects of aflibercept on the central nervous system, neuro-cognitive and motor skills do not lag behind chronologically, however, language skills in 80% of children have a slight lag, which may be due to a history of posthypoxic damage to the central nervous system in a premature baby