Selective down‐regulation of anti‐angiogenic splice variants of VEGF by IGF‐1 is mediated by PKC, PI‐3K and SRPK1/2

Abstract

VEGF, the predominant regulatory molecule in angiogenesis, is differentially spliced in its terminal exon (exon 8) to produce either pro‐angiogenic VEGFxxx or anti‐angiogenic VEGFxxxb isoforms. We have shown that IGF‐1 specifically down‐regulates VEGFxxxb expression in proliferating podocytes. Here, we investigated the role of PKC and PI‐3K in IGF‐1‐dependent down‐regulation of VEGFxxxb expression after 48 hours of treatment. VEGFxxxb proteins were measured in cell lysates by isoform‐specific ELISA. VEGFxxxb expression was decreased by IGF‐1 (0.28±0.05 fold to control). BIMI, an inhibitor of PKC kinases, prevented IGF‐1 down‐regulation of VEGFxxxb expression (1.14±0.04 fold to control). SRPIN340, an inhibitor of SRPK1/2 (serine‐arginine (SR) Protein Kinase 1 and 2) kinases implicated in splicing control by phosphorylating splicing factors, inhibited IGF‐1 down‐regulation of VEGFxxxb expression (1.17±0.14 fold). These results indicate that IGF‐1 decreases the synthesis of VEGFxxxb isoforms in proliferating podocytes through PKC, PI‐3K and SRPK1/2 kinases. Funded by the BHF (FS04/09, and BS06/005).