Vascular endothelial growth factor A isoform 165b (VEGF-A165b) (VEGF-A165b)

Vascular endothelial growth factor A isoform 165b (VEGF-A165b) is an endogenous, anti-angiogenic splice variant of the VEGFA gene, formed by the selection of a distal splice site in exon 8. Unlike the pro-angiogenic VEGF-A165a isoform, which promotes vessel growth and vascular permeability, VEGF-A165b acts as a dominant-negative or competitive inhibitor of the vascular endothelial growth factor receptor 2 (VEGFR2). While it binds to VEGFR2 with high affinity, it fails to induce the full receptor dimerization and autophosphorylation required for pro-angiogenic signaling, thereby dampening the effects of stimulatory isoforms. In healthy tissues, VEGF-A165b is often the predominant isoform, providing neuroprotection and maintaining vascular stability. However, its expression is frequently downregulated in pathological conditions such as cancer and diabetic retinopathy, where its absence facilitates excessive neovascularization. Conversely, its upregulation is observed in diseases characterized by impaired angiogenesis, such as systemic sclerosis and peripheral artery disease. Clinically, many anti-VEGF therapies like bevacizumab and aflibercept are pan-VEGF inhibitors that inadvertently neutralize VEGF-A165b, a factor that may contribute to therapeutic side effects such as neurotoxicity and impaired vascular repair.

Other names

VEGF165bVEGF-A165bVascular endothelial growth factor 165bAnti-angiogenic VEGF-AVEGF-A 165b

Drugs targeting this molecule, specifically pan-VEGF inhibitors like bevacizumab and aflibercept, act by binding and neutralizing the protein in the extracellular space, preventing its interaction with vascular endothelial growth factor receptors (VEGFRs). While these drugs primarily target pro-angiogenic isoforms, their high-affinity binding to VEGF-A165b leads to the unintended neutralization of its anti-angiogenic and neuroprotective signaling, shifting the local vascular balance.