Functional Overlap Between Chondroitin and Heparan Sulfate Proteoglycans During VEGF-Induced Sprouting Angiogenesis

Abstract

Objective Heparan sulfate proteoglycans (HSPGs) regulate key steps of blood vessel formation. The present study was undertaken to investigate if there is a functional overlap between HSPGs and chondroitin sulfate proteoglycans (CSPGs) during sprouting angiogenesis. Methods and Results Using cultures of genetically engineered mouse embryonic stem cells, we show that angiogenic sprouting occurs also in the absence of HS biosynthesis. Cells unable to produce HS instead increase their production of CS that binds key angiogenic growth factors such as VEGFA, TGFβ and PDGFB. Lack of HSPG production however leads to increased pericyte numbers and reduced adhesion of pericytes to nascent sprouts, likely due to dysregulation of TGFβ and PDGFB signal transduction. Conclusions The present study provides direct evidence for a previously undefined functional overlap between CSPGs and HSPGs during sprouting angiogenesis. Our findings provide information relevant for potential future drug design efforts that involve targeting of PGs in the vasculature.

Hepatocyte Heparan Sulfate Is Required for Adeno-Associated Virus 2 but Dispensable for Adenovirus 5 Liver Transduction In Vivo

“…Hepatocytes in Ext1 HEP mutant mice still express dermatan sulfate (DS) and chondroitin sulfate (CS), the other two major types of sulfated glycans. The lack of Ext1 leads to an increase in CS expression (48,49), which could potentially serve as the receptor for Ad.FX. However, mutant Ext1 Ϫ/Ϫ CHO pgsD-677 cells, although lacking heparan sulfate, contain three times the amount of CS and DS present in wild-type CHO K1 cells (34), and FX cannot increase Ad5 transduction of Ext1 Ϫ/Ϫ CHO cells (6,25).…”

Heparan Sulfate Biosynthesis

“…In this context, the finding of an interaction between EXT2 and N-deacetylase/Nsulfotransferase-1 (NDST1; see below) is interesting. Finally, EXT-mutant cells that do not synthesize HS instead produce increased amounts of CS Stickens et al 2005;Le Jan et al 2012). This interplay between HS and CS biosynthesis will be discussed further below.…”

Heparan sulfate in the regulation of neural differentiation and glioma development

“…Similarly to EXT1 knockout ESCs, NDST1/NDST2 doubleknockout cells also maintained their pluripotency in culture [37] but generally failed to differentiate upon EB formation [71]. Angiogenesis was severely delayed and adhesion of pericytes to nascent sprouting vessels was reduced in NDST1/NDST2 double-knockout EBs [72]. Somewhat surprisingly, these ESCs were able to generate osteoblasts, although with a lower efficacy than wild-type ESCs showing the ability to generate at least one kind of mesodermal cells, but they could not differentiate to adipocytes [73].…”