Endothelial Guidance in Vascular Patterning
Previous and current research
Blood vessels are a highly branched
system of continuous tubes with hierarchical organisation of tube size to ensure
directional flow and efficient perfusion of the entire organism. The patterning
of the vascular network is precisely adapted to specific functions and nutritional
demands of the different organs. In recent studies, we identified a mechanism
for precision guidance of the growing vascular sprout along gradients of growth
factors. Analogous to guidance of nerve fibres and guidance of airway
tubes in the fruit fly Drosophila, the vascular sprout is guided by long
filopodia extensions at the very tip that sense and navigate the tissue environment.
The tip cells differ from the following stalks cells also in gene expression,
proliferative quiescence, and in their response to the angiogenic factor - VEGF-A.
Detailed analysis of expression patterns at cellular resolution, analysis
of protein distribution and gradients, expression and activation of receptors
and a series of loss and gain of function experiments, have now provided evidence
that VEGF-A gradients are necessary and sufficient to guide endothelial sprouts
through stimulation and guidance of tip cell filopodia.
Future projects
We will apply the novel concept of
tip-cell guidance to study:
- gradient dependent guidance mechanisms;
- contact dependent guidance mechanisms;
- the role of preformed migration tracks and guide posts;
- the guidance of vascular fusion; and
- pathological patterning in neovascular disease.
We will address these questions by:
- high-resolution confocal microscopic analysis of the vasculature in mouse
mutants;
- by transcriptional profiling of tip-cells using microarray technique to
identify genes involved in the guidance process;
- by manipulating the dynamic behaviour of tip-cells in explants; and
- by studying gene-expression, protein distribution and cellular behaviour
in mouse models of human diseases which include neovascularisation such as
diabetic retinopathy and cancer.
