The heparan sulfate editing enzyme Sulf1 plays a novel role in zebrafish VegfA mediated arterial venous identity
The heparan sulfate editing enzyme Sulf1 plays a novel role in zebrafish VegfA mediated arterial venous identity
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DOI：
10.1007/s10456-013-9379-0
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发表时间：
2014-01-01
期刊：
影响因子：
9.8
通讯作者：
Stringer, Sally E.
中科院分区：
文献类型：
--
作者：
Gorsi, Bushra;Liu, Feng;Stringer, Sally E.
动脉和静脉特化对于建立和维持功能性血管系统至关重要，并且包括VEGF（血管内皮生长因子）在内的关键动静脉信号传导途径的缺陷导致先天性动脉病。VEGF的活性部分地由硫酸乙酰肝素（HS）蛋白聚糖（内皮糖萼的重要组分）控制。介导HS和VEGFA之间相互作用的HS多糖链上的6-O硫酸化水平在细胞表面由酶SULF 1编辑。我们研究了sulf 1在血管发育中的作用。在斑马鱼中，sulf 1在头部和尾部血管系统中表达，在空间和时间上与血管发育相对应。反义morpholinos靶向敲低sulf 1导致严重的血管图案和成熟缺陷。93%的磺基1吗啡啉在动脉发育中表现出畸形，导致远端主动脉闭塞以及缺乏轴向和颅侧循环。共注射vegfa（165）mRNA可挽救循环缺陷。虽然影响造血的基因没有改变，但在背主动脉中，VegfA信号传导下游的几种动脉标志物（如notch和ephrinB 2）的表达严重减少，同时在吗啡变体的背主动脉中静脉标志物flt 4的表达增加。此外，在体外，缺乏SULF 1表达下调VEGF介导的动脉标志物表达，证实Sulf 1通过调节VegfA（165）活性介导动脉特化。这项研究提供了第一个在体内的证据，内皮糖萼在指定动静脉身份，血管图案和动脉完整性的整体作用，并将有助于更好地了解先天性动脉病。
Arterial and venous specification is critical for establishing and maintaining a functioning vascular system, and defects in key arteriovenous signaling pathways including VEGF (vascular endothelial growth factor) lead to congenital arteriopathies. The activities of VEGF, are in part controlled by heparan sulfate (HS) proteoglycans, significant components of the endothelial glycocalyx. The level of 6-O sulfation on HS polysaccharide chains, that mediate the interaction between HS and VEGFA, is edited at the cell surface by the enzyme SULF1. We investigated the role of sulf1 in vascular development. In zebrafish sulf1 is expressed in the head and tail vasculature, corresponding spatially and temporally with vascular development. Targeted knockdown of sulf1 by antisense morpholinos resulted in severe vascular patterning and maturation defects. 93 % of sulf1 morphants show dysmorphogenesis in arterial development leading to occlusion of the distal aorta and lack of axial and cranial circulation. Co-injection of vegfa (165) mRNA rescued circulatory defects. While the genes affecting haematopoiesis are unchanged, expression of several arterial markers downstream of VegfA signalling such as notch and ephrinB2 are severely reduced in the dorsal aorta, with a concomitant increase in expression of the venous markers flt4 in the dorsal aorta of the morphants. Furthermore, in vitro, lack of SULF1 expression downregulates VEGFA-mediated arterial marker expression, confirming that Sulf1 mediates arterial specification by regulating VegfA(165) activity. This study provides the first in vivo evidence for the integral role of the endothelial glycocalyx in specifying arterial-venous identity, vascular patterning and arterial integrity, and will help to better understand congenital arteriopathies.