Regulation of human thyroid follicular cell function by inhibition of vascular endothelial growth factor receptor signalling

The potential autocrine role of human thyroid vascular endothelial growth factors (VEGFs) was examined using the VEGF receptor (VEGFR) inhibitor, ZM306416HCl. ZM306416HCl reduced VEGFR2 phosphorylation and inhibited endogenous, steady-state levels of p42/44 MAPK phosphorylation. It potently inhibited the secretion of plasminogen activators (PA) and increased (125)I uptake. Cell survival was compromised but rescued with insulin and TSH. Although the EGF receptor remained responsive to challenge by EGF in p42/44 MAPK assays, stimulatory effects of EGF on PA production were prevented by ZM306416HCl and those of protein kinase C stimulator, TPA reduced. In assays of (125)I uptake, ZM306416HCl prevented the inhibitory effects of EGF but not those of TPA. We conclude that autocrine VEGF may modulate thyroid function and that VEGFR inhibition increases iodide uptake and decreases PA production through regulation of p42/44 MAPK phosphorylation. VEGFR inhibition may have effects on thyroid function which may contribute to "off target" effects in clinical trials.