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SIRT1: a key modulator of blood vessel formation after birth
Genes & Dev. 2007 21: 2644-2658: “SIRT1 controls endothelial angiogenic functions during vascular growth” Collaborative work by Elisabetta Dejana.
A joint research among EVGN groups from the University of Frankfurt and IFOM – the FIRC Institute of Molecular Oncology Foundation - in collaboration with a group from Harvard University Medical School and the FUSAGx team in Belgium - proved that blood vessel formation that takes place after birth responds to a powerful conductor, an enzyme called SIRT1, that orchestrates a number of functions at endothelial level changing the expression profile of many endothelial genes. Published in the October issue of Genes & Development, the research could prospect new avenues of intervention in vascular-related pathologies, given the involvement of SIRT1 also in the metabolism of fatty acid and glucose.
The development and maturation of a functional vascular system is a complex and highly regulated process where signaling factors and molecules interact in a precise order. Alter one step upstream and you’ll unbalance many downstream reactions. Endothelial cells (ECs) play a pivotal role as they modulate the vascular system both during the initial formation and at later stages, when continuous remodeling is needed to adjust the vascular tree to novel functional needs. ECs, however, are highly interactive and respond to external signals too. Some of the stimuli ECs are sensitive to come from a family of seven proteins called sirtuins, so far poorly characterized at least with respect to their involvement in vascular homeostasis. In the present research, University of Frankfurt scientists Michael Potente and Stefanie Dimmeler with IFOM colleagues Elisabetta Dejana and Marina Mione focused on one of these proteins, SIRT1, an enzyme that proved to be much more active and powerful than previously envisaged.
“SIRT1 – explains PI Stefanie Dimmeler and EVGN scientist – is an enzyme recruited on specific DNA sites when it comes to inactivate the transcription of specific genes. Hence we decided to investigate if and how it affects the behaviour of ECs with respect to vascular development”. Using a disruptive technique called RNA interference, the scientists generated ECs unable to produce SIRT1 and observed that the cells were completely unable to sprout new vessels. “At this point we wanted to assess the properties of the SIRT1minus cells” says Dimmeler. “Not only we found that the cells were unable to form a vascular-like network in vitro, we also realized that they were incapable of responding to the common signals that, under physiological conditions, promote their migration and attract them to actively proliferating sites”.
Even more informative results were obtained when the teams exploited the properties of the Zebrafish embryo model, that allows real-time observation of ongoing processes. “Embryos where SIRT1 expression had been inhibited – observes Zebrafish group leader Marina Mione from IFOM – exhibited marked defects in the trunk vasculature and were subjected to frequent hemorrhages. A clear indication that, in the absence of SIRT1, maturation of the vascular system was incomplete”. Interestingly enough, defective embryos exhibited tip cells whose behaviour looked confused: “Instead of indicating the proper direction for sprouting, these guide-cells followed an irregular pathway and originated unwanted connections among vessels”.
The investigation of the role of SIRT1 in vascular homeostasis went further on. Using a complex strategy to inhibit SIRT1 only in the vascular endothelial cells of a mouse model, the scientists defined that, at early postnatal ages, the animals were unable to form new blood vessels when their tissues had suffered from ischemia, thus undergoing frequent necrotic events. “Macroscopic events reflect what happens at a molecular level” points out IFOM scientist Elisabetta Dejana. “And microarray analysis (a technique that provides a snapshot of the active/silent genes at specific time points) revealed that ECs in which SIRT1 had been silenced showed alterations in their gene expression pattern. Many genes involved in endothelial differentiation, remodeling or vascular development appeared down-regulated: an indication that they are controlled by SIRT1, the real supervisor of vascular homeostasis”.
“Taken together, this research expands the role of SIRT1 as a critical regulator of tissue homeostasis, and highlights the importance of team-working which is a consolidated approach of all the EVGN investigations” comments EVGN scientific coordinator Alan Tedgui, from INSERM, Paris. “Besides, it identifies a number of genes involved at different angiogenic phases that are under the control of SIRT1. Given the importance of SIRT1 in the process of neovascularization that occurs in the postnatal period, we might speculate about its possible involvement as therapeutic target in a number of vascular diseases”.
Genes & Dev. 2007 21: 2644-2658
“SIRT1 controls endothelial angiogenic functions during vascular growth”
Michael Potente, Laleh Ghaeni, Danila Baldessari, Raul Mostoslavsky, Lothar Rossig, Franck Dequiedt, Judith Haendeler, Marina Mione, Elisabetta Dejana, Frederick W. Alt, Andreas M. Zeiher and Stefanie Dimmeler.