Nuclear FAK and its kinase activity regulate VEGFR2 transcription in angiogenesis of adult mice.

ABSTRACT

Focal adhesion kinase (FAK) is essential in embryonic angiogenesis by regulating endothelial cell (EC) survival and barrier functions through its kinase-independent and -dependent activities. Here, we generated EC-specific tamoxifen-inducible FAK knockout and FAK kinase-defective (KD) mutant knockin mice to investigate the role of FAK and its kinase activity in angiogenesis of adult animals. Unlike previous observations of their differential defects in embryonic vascular development, both FAK ablation and inactivation of its kinase activity resulted in deficient angiogenesis in wound-healing as well as retinal angiogenesis models. Consistent with these phenotypes, loss of FAK or its kinase activity decreased EC proliferation and migration to similar extents, suggesting FAK primarily acts as a kinase for the regulation of adult EC-mediated angiogenesis. Further mechanistic analyses were carried out using an established mouse EC line MS1 cells. Interestingly, we found that FAK regulated the expression of VEGFR2, a central mediator of various EC functions and angiogenesis, which requires both FAK kinase activity and its translocation into the nucleus. Moreover, nuclear FAK was detected in the RNA polymerase II complex associated with VEGFR2 promoter, suggesting its direct participation in the transcriptional regulation of VEGFR2. Together, our results provide significant insights into the signaling mechanisms of FAK in angiogenesis that may contribute to future design of more effective angiogenesis related therapy.