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(Circulation Research. 2009;105:565.)
© 2009 American Heart Association, Inc.

Molecular Medicine

VEGF and RANKL Regulation of NFATc1 in Heart Valve Development

Michelle D. Combs, Katherine E. Yutzey

From the Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, Ohio.

Correspondence to Katherine E. Yutzey, Division of Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center ML7020, 240 Albert Sabin Way, Cincinnati, OH 45229. E-mail Katherine.Yutzey{at}cchmc.org

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 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.

Key Words: valve development • NFATc1 • VEGF • RANKL • JNK • ERK