VEGF and RANKL regulation of NFATc1 in heart valve development.
VEGF and RANKL regulation of NFATc1 in heart valve development.
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DOI：
10.1161/circresaha.109.196469
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发表时间：
2009-09-11
影响因子：
20.1
通讯作者：
Yutzey KE
中科院分区：
文献类型：
--
作者：
Combs MD;Yutzey KE
在心脏瓣膜发育过程中，内皮细胞垫（ECC）内皮细胞中的活化T细胞胞质核因子1（NFATc 1）活性是正常ECC生长和细胞外基质（ECM）重塑所必需的。在NFATc 1突变小鼠和鸡ECC外植体中检查NFATc 1激活和下游效应对细胞增殖和ECM重塑酶基因表达的机制。NFATc 1 −/−小鼠在胚胎第10.5天显示ECC内皮细胞和间充质细胞增殖减少，而心肌细胞不受影响。血管内皮生长因子A（VEGF）通过调节磷酸酶、钙调磷酸酶（Cn）和MAPK-ERK激酶1 -细胞外信号相关激酶1/2（MEK 1-ERK 1/2）依赖性信号传导激活NFATc 1并促进ECC细胞增殖。随着ECC成熟，ECC内皮细胞表达NFκB配体受体激活物（RANKL）和ECM重塑酶组织蛋白酶K（CtsK）。RANKL抑制VEGF诱导的细胞增殖，同时通过Cn/NFATc 1和c-Jun N末端激酶1/2（JNK 1/2）依赖性信号传导引起CtsK表达增加。这些数据支持了一种从ECC生长向重塑过渡的新机制，其中NFATc 1通过与配体特异性辅因子如MEK 1-ERK 1/2或JNK 1/2合作促进基因表达的顺序模式。
Nuclear Factor of Activated T-cells cytoplasmic 1 (NFATc1) activity in endocardial cushion (ECC) endothelial cells is required for normal ECC growth and extracellular matrix (ECM) remodeling during heart valve development. 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. NFATc1−/− mice display reduced proliferation of ECC endothelial and mesenchymal cells at embryonic day 10.5, while myocardial cells are unaffected. Vascular Endothelial Growth Factor A (VEGF) activates NFATc1 and promotes ECC cell proliferation via the regulatory phosphatase, Calcineurin (Cn), and MAPK-ERK Kinase 1 - Extracellular signal-Related Kinase 1/2 (MEK1-ERK1/2)-dependent signaling. As ECCs mature, Receptor Activator of NFκB Ligand (RANKL) 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 Cn/NFATc1 and c-Jun N-terminal Kinase 1/2 (JNK1/2)-dependent signaling. 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.