SPARC promotes angiogenesis and cell migration via VEGFR2-ERK1/2-SPHK1 axis in pterygium.

Pathological angiogenesis is a primary driver of pterygium progression, yet the mechanistic role of Secreted Protein Acidic and Rich in Cysteine (SPARC) remains to be fully elucidated. This study investigated the clinical significance and molecular function of SPARC in pterygium-associated neovascularization. Expression analysis in human pterygium tissues revealed a significant upregulation of SPARC, which positively correlated with lesion microvascular density as assessed by immunofluorescence and anterior segment optical coherence tomography angiography. Functionally, in vitro assays demonstrated that recombinant SPARC treatment robustly enhanced the migration, invasion, and tube-forming capacity of human umbilical vein endothelial cells (HUVECs), alongside elevated expression of the angiogenesis markers CD31 and α-SMA. Transcriptomic sequencing and Gene Set Enrichment Analysis (GSEA) identified a significant enrichment of SPARC-regulated genes within the vascular endothelial growth factor (VEGF) signaling pathway. Mechanistically, SPARC promoted Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) phosphorylation, triggering a sequential activation cascade of Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) and Sphingosine Kinase 1 (SPHK1). This pathway culminated in SPHK1 phosphorylation at Ser225 and increased production of the pro-angiogenic lipid mediator sphingosine-1-phosphate (S1P). Pharmacological inhibition of VEGFR2, ERK1/2, or SPHK1 attenuated these effects. In conclusion, this study provides a mechanistic validation of the SPARC/VEGFR2/ERK/SPHK1 signaling axis that drives pathological angiogenesis in pterygium, highlighting this cascade as a promising therapeutic target for clinical intervention.