Research topics
Molecular mechanisms of endothelial cell differentiation
and vessel maturation during angiogenesis. Background
Four biological phases of angiogenesis have been established
and characterized by different genetic programs. Initiation is the first
step, characterized by a endothelial cell shape change and increased permeability;
progression phase includes the degradation of extracellular matrix, migration
and proliferation of endothelial cells; in the differentiation phase endothelial
cells stop to growth and differentiate into primitive capillaries; maturation
phase includes the formation of new matrix and the recruitment of pericytes
and smooth muscle cells. The molecular mechanisms of differentiation and
maturation are largely unknown and need to be investigated to gain new insights
to use angiogenesis as a target for therapeutic intervention.
Achievements
(1) The role of small GTPases in models of endothelial
cell differentiation was evaluated by in vitro angiogenesis propelled by growth
factors or extracellular matrix proteins. We reached this aim using measurement
of enzymatic activities and of association to specific substrates; use of dominant
negative molecules; use of endothelial cells from knockout mice.
(2) Role of semaphorin-3 as an autocrine mediator of directional sprouting
and vessel remodelling. The hypothesis that semaphorin-3 is produced in discrete
areas of nascent vessels and that drives them through a pre-determinate route
was studied by using semaphorin-/- mice and dominant negative molecules in
avian systems.
Goals
(1) Role of angiopoietins and of their receptor (Tie-2)
in the maturation phase of angiogenesis by using in vitro and in vivo models.
The technique of phage display will be used to discover activating and inhibiting
peptides of angiopoietin/Tie-e pathway.
(2) Role of supramolecular membrane complex regulation of endothelial cell
behaviour.
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