The formation of mature blood vessels requires recruitment of mural cells (MC) and
generation of an extracellular matrix in order to stabilize and support the nascent vessel.
The precise sequence of basement membrane protein expression and function during
initiation, elongation and stabilization of the angiogenic sprout remains unclear.
The first project describes a function of astrocytic Fibronectin (FN) in guided
vessel migration. Integrin-binding is dispensable for fibrilliar FN assembly but mediates
endothelial cell adhesion in vivo. VEGF-A dependent migration of retinal vessels
requires PI3K activity and astrocytic FN possibly functions to retain VEGF protein on
the astrocytic matrix.
In a second project we discovered endothelial tip cells-specific expression of
laminin alpha4 (Lama4) and provide first evidence for an influence of laminin α4 on
endothelial Dll4/Notch signalling in sprouting angiogenesis. Loss of Lama4 leads to
increased filopodia formation, tip cell numbers and consequently increased vessel
density, resembling the phenotype of disturbed Dll4/Notch signalling. Loss of Lama4
leads to reduced Dll4 and Notch target gene expression, whereas gain-of-function
results in increased Dll4 expression in vitro. Preliminary results suggest that laminin α4
induced Dll4 expression involves both VEGFR2 and integrin signalling.
The third project addresses the cell-autonomous requirement of heparan sulfate
(HS) production by MCs during mouse embryonic vascular development. Conditional
deletion of HS synthesis in MC caused severe vascular defects and embryonic lethality.
Unexpectedly, distinct regions of vascular growth showed selective requirement for MC
HS production: whereas MC recruitment in peripheral skin vascularization is severely
disrupted, MCs during brain angiogenesis appear unaffected. Similarly, PDGF-B and
TGF-β signalling are impaired in the peripheral vessels, but not in the brain.
These data suggest that cell-autonomous HS is essential for MC recruitment in
the skin vasculature, where induction and differentiation of local progenitor cells from
the mesenchymal cell lineage is mediated by TGF-β signalling
