Holger Gerhardt : Vascular Biology

Goals

The density and branching pattern of blood vessels is precisely adapted to the function and metabolic needs of the organs they supply. Failure to establish a hierarchical branched blood vessel pattern leads to early embryonic lethality, or if occurring locally during disease processes, will cause severe complications. In cancer, blood vessels support tumour growth and provide, together with lymphatic vessels, the escape route for metastasis. Recent work illustrated the influence of the quantity and quality of these vessels on tumour growth and metastasis. However, the mechanisms controlling vascular patterning in development and disease are poorly understood.

Vascular patterning involves guided sprouting, branching and fusion to form the primary network, and subsequent remodelling through regulated regression. These processes are governed by orchestrated communication between cells in the tissue and the cells lining the blood vessels (endothelial cells). Tissues that receive insufficient oxygen or nutrient supply send out signals calling new blood vessels to sprout into this area. The sprouting response requires coordinated cell behaviour. Endothelial tip cells, endowed with particular cellular and molecular features, head each new vascular sprout. The following cells, called stalk cells, hold on tightly to each other and their leader through adhesion junctions. They form the vascular lumen and divide to provide new cells for tube extension.

Our studies address the mechanism of cell-cell communication and orchestrated endothelial cell behaviour. We rely on detailed observation of stereotyped vascular patterning in normal and genetically modified mouse retina, live observation of sprouting in zebrafish embryos, and analysis of cell fate in sprouting assays from mouse embryonic stems cells as well as computational modelling. Key questions relate to mechanisms of tip cell formation, specification and stabilization of stalk cells, and guidance of tip cell fusion during vascular development. In models of pathological blood vessel growth and cancer, we ask why patterning fails, and if tip cell guidance is disrupted. We will ultimately seek to refine anti-angiogenic therapy by selective targeting of endothelial tip cells and their function.