"**VEGF-A** is a **secreted dimeric growth factor** whose primary physiological role is to **activate endothelial cells** to support **vasculogenesis/angiogenesis** (development and remodeling of blood vessels) and to regulate vascular permeability. Mechanistically, VEGF-A ligands signal mainly through receptor tyrosine kinases **VEGFR1 (FLT1)** and **VEGFR2 (KDR/FLK1)**, with VEGFR2 functioning as the main pro-angiogenic signaling receptor."

"A key concept in VEGFA functional annotation is that it is not a single molecular species: **alternative splicing, extracellular processing, and even non-canonical translation** generate **forms with different diffusion/ECM retention properties and potentially different biological outputs**."

"- **VEGF121** is described as **freely diffusible**. (perezgutierrez2023biologyandtherapeutic pages 5-6) - **VEGF165** is **partly diffusible and partly HSPG-bound**, and ~half of secreted VEGF165 is diffusible while the remainder is HSPG-bound."

"**Receptors/co-receptors:** VEGF-A binds VEGF receptors **VEGFR1 and VEGFR2** and co-receptors **neuropilin-1 (NRP1) and neuropilin-2 (NRP2)**. Ligand binding triggers receptor **dimerization and transphosphorylation**."

"**VEGFR2 (KDR/FLK1) signaling outputs:** VEGFR2 activation engages multiple canonical pathways: - **PLCγ → PKC → ERK1/2**, associated with endothelial proliferation, migration, and broader endothelial homeostasis programs (including pro-angiogenic responses). (perezgutierrez2023biologyandtherapeutic pages 5-6) - **PI3K → AKT**, supporting survival and contributing to permeability regulation. (perezgutierrez2023biologyandtherapeutic pages 5-6) - **FAK signaling**, linked to ECM adhesion and vascular permeability."

"**VEGFR1 (FLT1) as regulator/decoy:** VEGFR1 can act as a **decoy receptor** limiting the amount of VEGF-A available to activate VEGFR2 in physiological contexts, and is generally characterized by weaker downstream activation (for example limited PLCγ–PKC–MAPK activation)."

"**Hypoxia-dependent transcription:** VEGFA is a canonical hypoxia-inducible gene regulated by **HIF1α/HIF2α** binding to a conserved hypoxia response element, and constitutive HIF stabilization (e.g., via loss of VHL function) can drive VEGFA upregulation even in normoxia."

"So-called **VEGFxxxb** transcripts (e.g., **VEGF165b**) have been discussed as anti-angiogenic competitors, but an authoritative 2023 review emphasizes that such variants are better regarded as **weak agonists rather than antagonists**, and their endogenous existence/importance remains debated."

"Under hypoxia, a **long VEGF-A isoform (“L-VEGF”)** can be translated from a **non-canonical upstream CUG start codon**, adding an N-terminal extension. L-VEGF can then be proteolytically cleaved upstream of the canonical VEGF-A start to produce two products: **(i) secreted VEGF-A**, and **(ii) an N-terminal fragment “N-VEGF” that can translocate to the nucleus**."

"- **N-VEGF** is **retained intracellularly** and can **translocate to the nucleus**. (katsman2022nvegftheautoregulatory pages 1-3) Primary experimental evidence shows that forcing N-VEGF into the nucleus (e.g., via NLS fusion) is sufficient to induce transcriptional programs including **Hif1α** and **VEGF-A isoforms** under normoxia, and that **genetic deletion** of N-VEGF changes a substantial fraction of the hypoxia-responsive transcriptome and increases susceptibility to hypoxia-associated apoptosis."

"VEGF-A–VEGFR2 signaling integrates multiple endothelial functions, including **proliferation/migration** (PLCγ–PKC–ERK), **survival** (PI3K–AKT), and **adhesion/permeability** (FAK-related signaling), providing a mechanistic explanation for why VEGFA is both a developmental angiogenesis factor and a mediator of pathological neovascularization and edema."