Stenzel, D.; (2009) Functional diversity of extracellular matrix components during vessel migration, endothelial sprouting and blood vessel stabilization. Doctoral thesis , UCL (University College London).

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Abstract

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.

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