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.

Improving therapies for tissue regeneration would significantly benefit healthcare worldwide. Millions of people 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 an effective healing process. However, therapeutic interventions trying to induce blood vessel growth have so far given disappointing results, and we still lack the proper understanding why this happens. 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. Surprisingly, its efficacy in clinical trials was below expectations and no benefit of VEGF therapy at safe doses could be found. High doses of VEGF induce an effect called non-productive angiogenesis, that is the presence of more but dysfunctional blood vessels, a phenomenon sometimes observed in tumors. In my research stay in the group of Dr Rui Benedito at the host institution CNIC in Madrid, I investigated why such strong angiogenic stimuli can lead to non-productive angiogenesis. Based on previous work published by the host, I looked at the connection between blood vessel growth and cell cycle regulation, a fundamental mechanism in cell biology to control cell division. During skin wound regeneration, I observed that certain blood vessels, which are very close to a wound, despite their high stimulus to proliferate, they stop growing. My research suggest that this is because they express specific proteins that are cellular gatekeepers and induce cell cycle arrest. If I further increase the angiogenic stimulation by genetically targeting components of the Notch pathway, this cell cycle arrest is even more pronounced. This means that instead of promoting blood vessel growth, a strong angiogenic stimulus actually leads to the opposite result. If the stimulus is more moderate, cell cycle arrest does not occur. This suggests that upon exceeding a certain threshold of intensity, a switch from productive to non-productive angiogenesis occurs. In my future research, I will look deeper into these mechanisms to find out why this is occurring during regeneration and if we can pharmacologically target these mechanisms to effectively boost angiogenesis and promote tissue growth.