DYRK1A kinase positively regulates angiogenic responses in endothelial cells

Abstract

Angiogenesis is a highly regulated process essential for organ development and maintenance, and its deregulation contributes to inflammation, cardiac disorders, and cancer. The Ca2+/nuclear factor of activated T cells (NFAT) signaling pathway is central to endothelial cell angiogenic responses, and it is activated by stimuli like vascular endothelial growth factor (VEGF) A. NFAT phosphorylation by dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) is thought to be an inactivating event. Contrary to expectations, we show that the DYRK family member DYRK1A positively regulates VEGF-dependent NFAT transcriptional responses in primary endothelial cells. DYRK1A silencing reduces intracellular Ca2+ influx in response to VEGF, which dampens NFAT activation. The effect is exerted at the level of VEGFR2 accumulation leading to impairment in PLCγ1 activation. Notably, Dyrk1a heterozygous mice show defects in developmental retinal vascularization. Our data establish a regulatory circuit, DYRK1A/ Ca2+/NFAT, to fine-tune endothelial cell proliferation and angiogenesis.

This work was supported by the Spanish Ministry of Economy and Competitiveness (MINECO grants BFU2013-44513 and BFU2016-76141-P to S.L., SAF2015-69762R to M.A.V., SAF2014-59950-P to M.G., BIO2014-57716-C2-R to C.F., and SAF2016-77971-R to M.L.A.), “La Marató de TV3” to S.L., the Instituto de Salud Carlos III (IIS10/00014 to C.F. and RD12/0042/0014 to M.A.V.), FEDER Funds to M.A.V., the Secretariat of Universities and Research-Generalitat de Catalunya (2014SGR674), the European CommissionFP7/2007-2013, and 2020 Research and Innovation Programmes (grant agreement 317250 and Marie Skłodowska-Curie grant agreement 675392). E.J.R., J.L., and M.J.B. are supported by CIBERER, J.R. is an FPI predoctoral fellow (BES-2011-045867), C.J. is a Juan de la Cierva postdoctoral researcher (JCI-2011-11140), and A.F.F. is a Marie Skłodowska-Curie ESR fellow.