Abstract
Perlecan is a heparan sulfate proteoglycan assembled into the vascular basement membranes (BMs) during vasculogenesis. In the present study we have investigated vessel formation in mice, teratomas and embryoid bodies (EBs) in the absence of perlecan. We found that perlecan was dispensable for blood vessel formation and maturation until embryonic day (E) 12.5. At later stages of development 40% of mutant embryos showed dilated microvessels in brain and skin, which ruptured and led to severe bleedings. Surprisingly, teratomas derived from perlecan-null ES cells showed efficient contribution of perlecan-deficient endothelial cells to an apparently normal tumor vasculature. However, in perlecan-deficient EBs the area occupied by an endothelial network and the number of vessel branches were significantly diminished. Addition of FGF-2 but not VEGF165 rescued the in vitro deficiency of the mutant ES cells. Furthermore, in the absence of perlecan in the EB matrix lower levels of FGFs are bound, stored and available for cell surface presentation. Altogether these findings suggest that perlecan supports the maintenance of brain and skin subendothelial BMs and promotes vasculo- and angiogenesis by modulating FGF-2 function.
Highlights
The formation of an elaborate vascular network is critical for development, tissue repair and tumor growth
Eosin staining revealed that wild type and perlecan-null teratomas were composed of a variety of differentiated cells and tissues including glandular structures, neuronal cell nests, muscle cells and areas of connective tissue (Fig. 3A,B)
In the present report we have investigated vascular development in mice, teratomas and embryoid bodies (EBs) lacking perlecan expression
Summary
The formation of an elaborate vascular network is critical for development, tissue repair and tumor growth. The vascular system forms by two different processes termed vasculo- and angiogenesis. During vasculogenesis mesenchymal progenitor cells differentiate into endothelial cells and establish a primitive vascular plexus. Angiogenesis occurs when endothelial cells start to proliferate and to sprout from preexisting vessels and thereby forming new vessels. The newly formed endothelial tubes mature by assembling a basement membrane (BM) and by recruiting smooth muscle cells or pericytes [1]. The formation and maturation of blood vessels are tightly controlled by a finely tuned balance of pro- and anti-angiogenic actions executed by growth factors, cell adhesion molecules and components of the extracellular matrix ECM
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