RESUMEN
The Notch signaling pathway is an important contributor to the development and homeostasis of the cardiovascular system. Not surprisingly, mutations in Notch receptors and ligands have been linked to a variety of hereditary diseases that impact both the heart and the vasculature. In particular, mutations in the gene encoding the human Notch ligand jagged 1 result in a multisystem autosomal dominant disorder called Alagille syndrome, which includes tetralogy of Fallot among its more severe cardiac pathologies. Jagged 1 is expressed throughout the developing embryo, particularly in endothelial cells. Here, we demonstrate that endothelial-specific deletion of Jag1 leads to cardiovascular defects in both embryonic and adult mice that are reminiscent of those in Alagille syndrome. Mutant mice display right ventricular hypertrophy, overriding aorta, ventricular septal defects, coronary vessel abnormalities and valve defects. Examination of mid-gestational embryos revealed that the loss of Jag1, similar to the loss of Notch1, disrupts endothelial-to-mesenchymal transition during endocardial cushion formation. Furthermore, adult mutant mice exhibit cardiac valve calcifications associated with abnormal matrix remodeling and induction of bone morphogenesis. This work shows that the endothelium is responsible for the wide spectrum of cardiac phenotypes displayed in Alagille Syndrome and it demonstrates a crucial role for Jag1 in valve morphogenesis.
Asunto(s)
Síndrome de Alagille/genética , Calcinosis/genética , Proteínas de Unión al Calcio/genética , Cardiomiopatías/genética , Cardiopatías Congénitas/genética , Enfermedades de las Válvulas Cardíacas/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas de la Membrana/genética , Animales , Proteínas de Unión al Calcio/metabolismo , Cardiomiopatías/metabolismo , Anomalías de los Vasos Coronarios/genética , Anomalías de los Vasos Coronarios/metabolismo , Células Endoteliales/citología , Células Endoteliales/metabolismo , Endotelio/citología , Endotelio/metabolismo , Cardiopatías Congénitas/metabolismo , Defectos del Tabique Interventricular/genética , Defectos del Tabique Interventricular/metabolismo , Enfermedades de las Válvulas Cardíacas/metabolismo , Hipertrofia Ventricular Derecha/genética , Hipertrofia Ventricular Derecha/metabolismo , Proteína Jagged-1 , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Morfogénesis , Técnicas de Cultivo de Órganos , Receptores Notch/genética , Receptores Notch/metabolismo , Proteínas Serrate-JaggedRESUMEN
The integrity of the endothelial monolayer is essential to blood vessel homeostasis and active regulation of endothelial permeability. The FGF system plays important roles in a wide variety of physiologic and pathologic conditions; however, its role in the adult vasculature has not been defined. To assess the role of the FGF system in the adult endothelial monolayer, we disrupted FGF signaling in bovine aortic endothelial cells and human saphenous vein endothelial cells in vitro and in adult mouse and rat endothelial cells in vivo using soluble FGF traps or a dominant inhibitor of all FGF receptors. The inhibition of FGF signaling using these approaches resulted in dissociation of the VE-cadherin/p120-catenin complex and disassembly of adherens and tight junctions, which progressed to loss of endothelial cells, severe impairment of the endothelial barrier function, and finally, disintegration of the vasculature. Thus, FGF signaling plays a key role in the maintenance of vascular integrity.