Participants

Juan Miguel Redondo and collaborators Juan Miguel Redondo Centro Nacional de Investigaciones Cardiovasculares CNIC Regulation of Gene Expression in Vascular Endothelium

The Ca2+/Calcineurin/NFAT pathway is involved in a plethora of highly relevant biological processes that include the development and activation of the immune, vascular and nervous systems, and the morphogenesis of the heart valves. Furthermore, this pathway is also involved in the hypertrophy of cardiac and skeletal muscle, and it plays an important role in angiogenesis and β-cell growth and function in pancreas. In addition, this pathway regulates bone mass in mice.

In the endothelium, VEGF (Vascular Endothelial Growth Factor) activates the CN/NFAT pathway upon binding to the tyrosine kinase receptor Flk-1/KDR. Simultaneously, the expression of this receptor is regulated by the transcription factor HRT1/Hey1, a Notch target. On the other hand, mice with targeted mutations for Notch, CnB or NFAT show similar defects in the vasculature and cardiac development. NFAT regulates pattern formation in the endothelium, suggesting that the functional relationship between Notch and NFAT is essential for proper vascular development. Our first aim is to characterize the relation between Notch and NFAT in the endothelium, identifying the conjunction elements between both pathways and its potential modulation.

In this project, we are also dealing with the study of the effects of activated and dominant negative forms of components of this pathway, and its role in the development and treatment of cardiac hypertrophy. Given that CsA, the classical inhibitor of Calcineurin, prevents cardiac hypertrophy, and transgenic mice overexpressing NFAT in the heart develop hypertrophy, it might be expected that the infection of cardiomyocytes with viral vectors expressing inactive CN (dominant negative), or with vectors expressing the sequences involved in the interaction of CN with NFAT, would not only prevent cardiac hypertrophy but also, that these constructs may have a therapeutic effect once the pathology has been established.

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