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 beta 4. 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 alpha 1 and beta 5, decreased the expression of integrins alpha 2 and beta 3, but had some or no effect on the expression of integrins alpha v, alpha 3, alpha 4, alpha 5, alpha 6,beta 1 and beta 7. In the angiogenic responses mediated by TR3/Nur77, integrin alpha 1 regulated endothelial cell proliferation and adhesion, but not migration. Integrin beta 5 shRNA inhibited cell migration, but increased proliferation and adhesion. Integrin alpha 2 regulated all of the endothelial cell proliferation, migration and adhesion. However, integrin beta 3 did not play any role in endothelial cell proliferation, migration and adhesion. TR3/Nur77 regulated the transcription of integrins alpha 1, alpha 2, beta 3 and beta 5, via various amino acid fragments within its transactivation domain and DNA binding domain. Furthermore, TR3/Nur77 regulated the integrin alpha 1 promoter activity by directly interacting with a novel DNA element within the integrin alpha 1 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.