VEGFA

Overview

Vascular endothelial growth factor A (VEGFA) is a key signaling protein that plays a crucial role in angiogenesis, the process of new blood vessel formation from pre-existing vessels. It is part of the VEGF family, which includes several other growth factors that regulate vascular development and permeability. VEGFA primarily acts by binding to its receptors, VEGFR-1 and VEGFR-2, which are expressed on endothelial cells. This interaction stimulates endothelial cell proliferation, migration, and survival, thereby promoting the formation of new blood vessels. Due to its significant role in angiogenesis, VEGFA is a critical target in various therapeutic strategies, particularly in cancer treatment, where tumor growth and metastasis are often dependent on angiogenesis.

Focus of Latest Publications

Recent studies have explored diverse therapeutic strategies targeting VEGFA across multiple disease contexts. In retinal disease, neutralizing antibodies against VEGFA—including aflibercept, faricimab, and anti-VEGFA/ANG-2 bispecific antibodies—have demonstrated efficacy in suppressing pathological neovascularization and restoring endothelial barrier function in oxygen-induced retinopathy and neovascular age-related macular degeneration. Novel gene-editing approaches have also emerged, including CRISPR/Cas9 delivery via ionizable lipid nanoparticles designed to knockout the VEGFA gene itself, which reduced pathological neovascularization and retinal leakage in diabetic retinopathy models while maintaining biocompatibility. Beyond antibodies, receptor-based antagonism using VEGFR-1 decoy receptors (PB101) has been investigated for broader anti-angiogenic effects in gastric cancer by simultaneously inhibiting VEGF-A, VEGF-B, and PlGF. In cancer immunotherapy, bispecific antibodies simultaneously targeting VEGF-A and immune checkpoints—such as ivonescimab targeting PD-1/VEGF-A—have shown activity in metastatic cervical cancer and other solid tumors through combined angiogenic inhibition and immune checkpoint blockade.

In contrast, VEGFA promotion has been pursued for tissue regeneration and wound healing. Bioactive hydrogels co-delivering VEGFA and bFGF genes via nanoparticles combined with platelet-rich plasma have been designed to accelerate full-thickness skin wound healing. In neonatal hypoxic-ischemic brain injury, therapeutic magnetic nanovesicles enhanced endothelial survival and angiogenic repair through activation of the ITGB3/VEGFA signaling axis, promoting vascular recovery and neurological improvement. mesenchymal stem cell therapies promoting CD73 expression have been shown to upregulate VEGFA via hypoxia-inducible factor-1α-dependent pathways, enhancing angiogenesis and wound closure in diabetic pressure ulcer models.

VEGFA dysregulation has been identified as a driver of disease progression across multiple malignancies. In head and neck squamous cell carcinoma, hypoxia upregulates the MSC-AS1/ITGA5 axis, increasing VEGFA and PD-L1 expression and correlating with an immunosuppressive microenvironment. In diabetic retinopathy, lactate accumulation promotes HMGA1 lactylation at lysine 74, which enhances specificity protein 1–mediated VEGFA transcription and vascular dysfunction. In clear cell renal cell carcinoma, multi-omics analyses identified FLT1 as a central hub gene closely associated with VEGFA and Akt1, mediating epithelial-endothelial crosstalk that drives tumor progression; patients with high FLT1 expression were associated with poor immunotherapy responses. VEGFA expression has also been observed during cervical cancer progression and identified as a biomarker in hepatic neuroendocrine tumors, supporting its role as both a prognostic indicator and therapeutic target.

Emerging approaches combine VEGFA-targeting with complementary mechanisms to enhance therapeutic efficacy. In triple-negative breast cancer, fucoidan-modified nanoparticles targeting P-selectin suppress VEGF-A-mediated angiogenesis independently while simultaneously promoting M1 macrophage polarization. In renal cell carcinoma, integrative multi-target inhibitors (RING1) incorporating VEGF/Tie2-targeting modules self-assemble into nanonetworks that achieve prolonged tumor retention and enhanced vascular normalization alongside immune checkpoint blockade, demonstrating superior efficacy to conventional combination therapies. These findings collectively establish VEGFA as a critical nexus linking angiogenesis, immune regulation, and tissue homeostasis, with therapeutic strategies spanning antagonism for disease suppression and selective promotion for regenerative repair.