Blood vessels are a major player in cancer or cardiovascular disease. Tumors can only develop and spread when blood vessels are formed. The formation of new blood vessels is a process named as angiogenesis, and it supports tumor or tissue growth. In cardiovascular disease or in wounds, the induction of angiogenesis can be beneficial to improve tissue vascularization and function.
Research in the last years identified the major molecular mechanisms controlling angiogenesis, and showed us what to expect from targeting those mechanisms during cancer development or after cardiovascular ischemia. In general, scientists have succeeded in effectively blocking angiogenesis, which has been shown to delay tumor growth and sometimes prevent metastasis. However, inducing effective or productive angiogenesis in ischemic or damaged tissues has been a much more difficult task. An easy to understand comparison is that is much easier to demolish than build a house.
One of the main goals of this ERC Consolidator project is to identify new genetic and pharmacologically targetable mechanisms to induce effective angiogenesis in normal or ischemic/damaged tissues. In the last years scientists identified specific growth or inhibitory factors of angiogenesis. Therefore, adding the identified growth factors or specifically blocking their inhibitors was explored in clinical settings. However, in most cases the results were disappointing. Before the start of this project, our laboratory found that whenever angiogenesis is stimulated above a certain threshold, vessels upregulate the expression of molecules that block their own proliferation. These are called proliferation checkpoints, and are considered to protect cells from DNA damage. In our lab, we knew that vascular cells can proliferate and have a normal function without some of these overprotective checkpoints. Therefore, one of the goals of this project was to test if we could boost therapeutic angiogenesis by preventing the function of some of these proliferation checkpoints.
The second major goal of this project was to understand how vessels form, proliferate and distribute their building blocks across tissues, during organ development, homeostasis or in disease. Our laboratory developed in the last years unique genetic technologies that allow us to follow how every single cell of blood vessels clonally expand and migrate in a mouse. This allowed us to see that each individual vascular cell has unique properties. Some cells clonally expand immensely more than most of their neighbours. We are trying to discover and understand the genetic and epigenetic mechanisms responsible for that cell-to-cell difference in proliferation, in order to find new ways to promote it. We also identified mechanisms responsible for the mobilization of vascular cells across a growing vasculature. Some cells tend to form arteries, whereas others veins, and this can be changed pharmacologically. This will help us to better understand the origin and development of human arteriovenous malformations (AVMs), and also design better therapies to promote the formation of functional blood vessels in disease.
