Mechanisms of cell-cycle arrest of endothelial cells

Improving therapies that address tissue regeneration is a crucial issue in healthcare worldwide. Several million people have to suffer the consequences of inadequate tissue healing for instance after injury, surgery or after a heart attack. One commonality of impaired tissue regeneration is the lack of appropriate blood vessel growth. The generation of new functional blood vessels is essential for healing processes as almost all tissues are dependent on an adequate blood supply. The formation of new blood vessels strongly depends on the availability of the growth factor VEGF. Hence, it was believed that application of VEGF would be beneficial for tissue regeneration in humans. However, its efficacy in clinical trials was below expectations and no benefit of VEGF therapy at safe doses could be found. Follow-up studies discovered the requirement for tightly regulated VEGF concentrations for proper vascular development. Addressing this issue and investigating the underlying mechanisms could therefore result in significant improvement of angiogenic therapies. The group of Dr. Rui Benedito at the host institution CNIC has found that high VEGF doses initiate the formation of new blood vessels but ultimately blocks their growth, thereby potentially explaining the failure of VEGF therapy observed in clinics. This is at least in part mediated by specific cell growth inhibitor proteins such as p21. To investigate this further, the applicant Dr. Severin Mühleder proposes a research project where he plans to use state-of-the-art genetic tools developed at the host institution to study the role of factors that influence cell growth during formation of new blood vessels. The results generated in this proposed 2-year research project will be of crucial interest to the scientific community as these findings will significantly contribute to improved understanding of the biology of blood vessels and increase the effectiveness of VEGF and tissue regeneration therapies.

No additional funding sources recorded.