Orphan nuclear receptor TR3/Nur77 differentially regulates the expression of integrins in angiogenesis.

Pathological angiogenesis is a hallmark of many diseases. Previously, we reported that orphan nuclear receptor TR3/Nur77 (human homolog, Nur77, mouse homolog) is a critical mediator of angiogenesis to regulate tumor growth and skin wound healing via down-regulating the expression of the junctional proteins and integrin β4. However, the molecular mechanism, by which TR3/Nur77 regulated angiogenesis, was still not completely understood. In this report by analyzing the integrin expression profile in endothelial cells, we found that the TR3/Nur77 expression highly increased the expression of integrins α1 and β5, decreased the expression of integrins α2 and β3, but had some or no effect on the expression of integrins αv, α3, α4, α5, α6, β1 and β7. In the angiogenic responses mediated by TR3/Nur77, integrin α1 regulated endothelial cell proliferation and adhesion, but not migration. Integrin β5 shRNA inhibited cell migration, but increased proliferation and adhesion. Integrin α2 regulated all of the endothelial cell proliferation, migration and adhesion. However, integrin β3 did not play any role in endothelial cell proliferation, migration and adhesion. TR3/Nur77 regulated the transcription of integrins α1, α2, β3 and β5, via various amino acid fragments within its transactivation domain and DNA binding domain. Furthermore, TR3/Nur77 regulated the integrin α1 promoter activity by directly interacting with a novel DNA element within the integrin α1 promoter. These studies furthered our understanding of the molecular mechanism by which TR3/Nur77 regulated angiogenesis, and supported our previous finding that TR3/Nur77 was an excellent therapeutic target for pathological angiogenesis. Therefore, targeting TR3/Nur77 inhibits several signaling pathways that are activated by various angiogenic factors.