VEGF165

VEGF165 is a major isoform of vascular endothelial growth factor A (VEGF-A), a secreted glycoprotein that drives angiogenesis. It consists of 165 amino acids and is produced by alternative splicing of the VEGFA gene. VEGF-A isoforms, including VEGF-A165, typically function as homodimers and differ in their affinity for heparin and extracellular matrix components due to the presence or absence of a heparin-binding domain in certain isoforms.

VEGF165 signals primarily through VEGF receptor-2 (VEGFR-2/KDR/Flk-1) and to a lesser extent through VEGF receptor-1 (VEGFR-1/FLT1). Binding activates signaling cascades such as PLCγ-PKC, PI3K-Akt, and MAPK, promoting endothelial cell proliferation, migration, and survival. Neuropilins (NRP1 and NRP2) act as co-receptors, enhancing these signals and increasing overall angiogenic potency.

Biological roles include promotion of angiogenesis and increased vascular permeability. In development, VEGF165 is essential for the formation of the vasculature; in adults, it participates in wound healing and reproductive processes, while in disease it contributes to pathological neovascularization seen in cancer, diabetic retinopathy, and age-related macular degeneration.

Regulation: VEGF-A165 expression is upregulated by hypoxia via HIF-1 and by other pro-angiogenic stimuli. It is one of several VEGF-A isoforms; others such as VEGF-A121 and VEGF-A189 differ in extracellular matrix binding. An anti-angiogenic variant, VEGF-A165b, can be produced by alternative splicing of exon 8 and counteracts some signaling.

Clinical relevance: Because VEGF-A165 is a key driver of pathological neovascularization, it is a major therapeutic target. Anti-VEGF therapies, including bevacizumab, ranibizumab, and aflibercept, aim to neutralize VEGF-A isoforms and are used to treat cancer and retinal diseases characterized by unwanted vessel growth.