Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development
Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development
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DOI：
10.1101/gad.398207
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发表时间：
2007-02-01
影响因子：
10.5
通讯作者：
Gerhardt, Holger
中科院分区：
文献类型：
--
作者：
Abramsson, Alexandra;Kurup, Sindhulakshmi;Gerhardt, Holger
在血管发育过程中，内皮血小板衍生生长因子B（PDGF-B）对周细胞募集至关重要。保守的C-末端肝素结合基序的缺失损害体内PDGF-BB的保留和周细胞募集，表明硫酸乙酰肝素（HS）在血管发育过程中PDGF-BB功能中的潜在作用。我们研究了参与HS链周细胞招聘使用两个小鼠模型与改变HS生物合成。由于N-脱乙酰基酶/N-磺基转移酶-1的缺乏而导致的N-硫酸化的减少在体外减弱了PDGF-BB结合，并导致周细胞脱离和延迟的周细胞迁移。减少的N-硫酸化也损害PDGF-BB信号传导和指导细胞迁移，但不增殖。相比之下，HS从葡萄糖醛酸C5-差向异构酶突变体，这是广泛的N-和6-O-硫酸化，但缺乏2-O-硫酸化的L-艾杜糖醛酸残基，保留PDGF-BB在体外，和周细胞在体内的招聘只是暂时延迟。这些观察结果得到了对PDGF-BB结合重要的HS结构特征的体外表征的支持。我们得出结论，周细胞募集需要具有充分延伸和适当间隔的N-硫酸化结构域的HS，以保留PDGF-BB并激活PDGF受体β（PDGFR β）信号传导，而单糖和硫酸酯残基的详细序列似乎对这种相互作用并不重要。
During vascular development, endothelial platelet-derived growth factor B (PDGF-B) is critical for pericyte recruitment. Deletion of the conserved C-terminal heparin-binding motif impairs PDGF-BB retention and pericyte recruitment in vivo, suggesting a potential role for heparan sulfate (HS) in PDGF-BB function during vascular development. We studied the participation of HS chains in pericyte recruitment using two mouse models with altered HS biosynthesis. Reduction of N-sulfation due to deficiency in N-deacetylase/N-sulfotransferase-1 attenuated PDGF-BB binding in vitro, and led to pericyte detachment and delayed pericyte migration in vivo. Reduced N-sulfation also impaired PDGF-BB signaling and directed cell migration, but not proliferation. In contrast, HS from glucuronyl C5-epimerase mutants, which is extensively N- and 6-O-sulfated, but lacks 2-O-sulfated L-iduronic acid residues, retained PDGF-BB in vitro, and pericyte recruitment in vivo was only transiently delayed. These observations were supported by in vitro characterization of the structural features in HS important for PDGF-BB binding. We conclude that pericyte recruitment requires HS with sufficiently extended and appropriately spaced N- sulfated domains to retain PDGF-BB and activate PDGF receptor beta (PDGFR beta) signaling, whereas the detailed sequence of monosaccharide and sulfate residues does not appear to be important for this interaction.