Rudbeck Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Arterioscler Thromb Vasc Biol. 2012 May;32(5):1255-63. doi: 10.1161/ATVBAHA.111.240622. Epub 2012 Feb 16.
Heparan sulfate proteoglycans regulate key steps of blood vessel formation. The present study was undertaken to investigate if there is a functional overlap between heparan sulfate proteoglycans and chondroitin sulfate proteoglycans during sprouting angiogenesis.
Using cultures of genetically engineered mouse embryonic stem cells, we show that angiogenic sprouting occurs also in the absence of heparan sulfate biosynthesis. Cells unable to produce heparan sulfate instead increase their production of chondroitin sulfate that binds key angiogenic growth factors such as vascular endothelial growth factor A, transforming growth factor β, and platelet-derived growth factor B. Lack of heparan sulfate proteoglycan production however leads to increased pericyte numbers and reduced adhesion of pericytes to nascent sprouts, likely due to dysregulation of transforming growth factor β and platelet-derived growth factor B signal transduction.
The present study provides direct evidence for a previously undefined functional overlap between chondroitin sulfate proteoglycans and heparan sulfate proteoglycans during sprouting angiogenesis. Our findings provide information relevant for potential future drug design efforts that involve targeting of proteoglycans in the vasculature.
硫酸乙酰肝素蛋白聚糖调控血管生成的关键步骤。本研究旨在探讨在血管发芽过程中硫酸乙酰肝素蛋白聚糖和软骨素硫酸蛋白聚糖之间是否存在功能重叠。
利用基因工程鼠胚胎干细胞培养物，我们发现即使没有硫酸乙酰肝素生物合成，血管生成也会发生发芽。不能产生硫酸乙酰肝素的细胞反而会增加其软骨素硫酸盐的产生，这种硫酸盐可以结合关键的血管生成生长因子，如血管内皮生长因子 A、转化生长因子β和血小板衍生生长因子 B。然而，缺乏硫酸乙酰肝素蛋白聚糖的产生会导致周细胞数量增加，周细胞与新生芽的黏附减少，这可能是由于转化生长因子β和血小板衍生生长因子 B 信号转导的失调。
本研究为在血管发芽过程中软骨素硫酸蛋白聚糖和硫酸乙酰肝素蛋白聚糖之间存在以前未定义的功能重叠提供了直接证据。我们的发现为未来涉及血管中蛋白聚糖靶向的潜在药物设计提供了相关信息。
