VEGF and RANKL Regulation of NFATc1 in Heart Valve Development

Publisher Website
Google Scholar
Abstract
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 κB ligand) and the ECM-remodeling enzyme cathepsin K (CtsK) are e...