Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function

被引:484
作者
Serini, G [1 ]
Valdembri, D
Zanivan, S
Morterra, G
Burkhardt, C
Caccavari, F
Zammataro, L
Primo, L
Tamagnone, L
Logan, M
Tesssier-Lavigne, M
Taniguchi, M
Püschel, AW
Bussolino, F
机构
[1] Univ Turin, Sch Med, Div Mol Angiogenesis, I-10060 Candiolo, TO, Italy
[2] Univ Turin, Sch Med, Inst Canc Res & Treatment, IRCC,Div Mol Oncol, I-10060 Candiolo, TO, Italy
[3] Univ Turin, Sch Med, Dept Oncol Sci, I-10060 Candiolo, TO, Italy
[4] Univ Munster, Inst Allgemeine Zool & Genet, Mol Biol Abt, D-48149 Munster, Germany
[5] Natl Inst Med Res, Div Dev Biol, London NW7 1AA, England
[6] Stanford Univ, Howard Hughes Med Inst, Dept Biol Sci, Stanford, CA 94305 USA
[7] Univ Tokyo, Grad Sch Med, Dept Biochem & Mol Biol, Bunkyo Ku, Tokyo 1130033, Japan
基金
美国国家卫生研究院;
关键词
D O I
10.1038/nature01784
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The motility and morphogenesis of endothelial cells is controlled by spatio-temporally regulated activation of integrin adhesion receptors, and integrin activation is stimulated by major determinants of vascular remodelling. In order for endothelial cells to be responsive to changes in activator gradients, the adhesiveness of these cells to the extracellular matrix must be dynamic, and negative regulators of integrins could be required. Here we show that during vascular development and experimental angiogenesis, endothelial cells generate autocrine chemorepulsive signals of class 3 semaphorins (SEMA3 proteins) that localize at nascent adhesive sites in spreading endothelial cells. Disrupting endogenous SEMA3 function in endothelial cells stimulates integrin-mediated adhesion and migration to extracellular matrices, whereas exogenous SEMA3 proteins antagonize integrin activation. Misexpression of dominant negative SEMA3 receptors in chick embryo endothelial cells locks integrins in an active conformation, and severely impairs vascular remodelling. Sema3a null mice show vascular defects as well. Thus during angiogenesis endothelial SEMA3 proteins endow the vascular system with the plasticity required for its reshaping by controlling integrin function.
引用
收藏
页码:391 / 397
页数:7
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