VEGF and RANKL Regulation of NFATc1 in Heart Valve Development

Rationale: NFATc1 ( nuclear factor of activated T-cells cytoplasmic 1) activity in endocardial cushion (ECC) endothelial cells is required for normal ECC growth and extracellular matrix (ECM) remodeling during heart valve development. Objective: The mechanisms of NFATc1 activation and downstream effects on cell proliferation and ECM-remodeling enzyme gene expression were examined in NFATc1 mutant mice and chick ECC explants. Methods and Results: NFATc1(-/-) mice display reduced proliferation of ECC endothelial and mesenchymal cells at embryonic day 10.5, whereas myocardial cells are unaffected. Vascular endothelial growth factor A ( VEGF) activates NFATc1 and promotes ECC cell proliferation via the regulatory phosphatase, calcineurin, and mitogen-activated protein kinase-extracellular signal-regulated kinase 1-extracellular signal-regulated kinase 1/2 (MEK1-ERK1/2)-dependent signaling. As ECCs mature, RANKL ( receptor activator of nuclear factor kappa B ligand) and the ECM-remodeling enzyme cathepsin K (CtsK) are expressed by ECC endothelial cells. RANKL inhibits VEGF-induced cell proliferation while causing increased expression of CtsK via calcineurin/NFATc1 and c-Jun N-terminal kinase (JNK) 1/2-dependent signaling. Conclusion: These data support a novel mechanism for the transition from ECC growth to remodeling in which NFATc1 promotes a sequential pattern of gene expression via cooperation with ligand-specific cofactors such as MEK1-ERK1/2 or JNK1/2. ( Circ Res. 2009; 105: 565-574.)