RESUMO
Angiogenesis contributes to the development of numerous disorders. Even though fibroblast growth factors (FGFs) were discovered as mediators of angiogenesis more than 30 years ago, their role in developmental angiogenesis still remains elusive. We use a recently described chemical probe, SSR128129E (SSR), that selectively inhibits the action of multiple FGF receptors (FGFRs), in combination with the zebrafish model to examine the role of FGF signaling in vascular development. We observe that while FGFR signaling is less important for vessel guidance, it affects vascular outgrowth and is especially required for the maintenance of blood vessel integrity by ensuring proper cell-cell junctions between endothelial cells. In conclusion, our work illustrates the power of a small molecule probe to reveal insights into blood vessel formation and stabilization and thus of broad interest to the vascular biology community.
Assuntos
Vasos Sanguíneos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Nadadeiras de Animais/fisiologia , Animais , Vasos Sanguíneos/efeitos dos fármacos , Caderinas/metabolismo , Embrião não Mamífero/metabolismo , Indolizinas/química , Indolizinas/metabolismo , Indolizinas/farmacologia , Junções Intercelulares/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Regeneração , Transdução de Sinais/efeitos dos fármacos , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/antagonistas & inibidores , ortoaminobenzoatos/química , ortoaminobenzoatos/metabolismo , ortoaminobenzoatos/farmacologiaRESUMO
Receptor tyrosine kinases (RTK) are targets for anticancer drug development. To date, only RTK inhibitors that block orthosteric binding of ligands and substrates have been developed. Here, we report the pharmacologic characterization of the chemical SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling by binding to the extracellular FGFR domain without affecting orthosteric FGF binding. SSR exhibits allosteric properties, including probe dependence, signaling bias, and ceiling effects. Inhibition by SSR is highly conserved throughout the animal kingdom. Oral delivery of SSR inhibits arthritis and tumors that are relatively refractory to anti-vascular endothelial growth factor receptor-2 antibodies. Thus, orally-active extracellularly acting small-molecule modulators of RTKs with allosteric properties can be developed and may offer opportunities to improve anticancer treatment.