Defining the role of the histone deacetylase SIRT1 for the regulation of endothelial cell function and postnatal vessel formation.

• Applicant: Professor Dr. Michael Potente
• Subject Area: Cardiology, Angiology
• Term: from 2007 to 2010
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 35551396

The histone deacetylase Sir2 is a key regulator of lifespan inducing longevity in model organisms such as S. cerevisiae and C. elegans. Mammalian homologues of Sir2 are called sirtuins, among which SIRT1 is the closest homologue of Sir2. SIRT1 has been shown to play a critical role in the regulation of senescence, differentiation and metabolism by targeting transcription factors for deacetylation. However, the role of sirtuins for endothelial cell function and vascular homeostasis remains virtually unknown. In a genetic screen to study in detail the role of sirtuins in endothelial cells, we found that specifically SIRT1 plays a key role in the regulation of the angiogenic activity of endothelial cells. SIRT1 is highly expressed in cultured endothelial cells as well as in intact blood vessels in vivo. Blocking SIRT1 activity by either pharmacological inhibition or RNA interference abrogated the migratory and sprout forming activity of endothelial cells, whereas stimulation of SIRT1 activity by either treatment with the known sirtuin activator resveratrol or overexpression of SIRT1 led to an enhanced angiogenic response. The object of the present research proposal is to further characterize the role of SIRT1 in the formation, growth and maturation of the adult vasculature. To explore this model, we propose 1.) to define the in vivo relevance of SIRT1 for the regulation of postnatal vessel growth and maturation, 2.) to identify the molecular targets and signaling networks of SIRT1, and 3.) to characterize signaling pathways regulating the activity and expression of SIRT1 in vascular endothelial cells. To address these aims, we will combine in vitro and in vivo assays and employ state of the art techniques. Our hypothesis is that SIRT1 functions as an essential regulator of endothelial gene expression governing postnatal vascular growth and differentiation.

• DFG Programme: Research Grants