Vasorin, a transforming growth factor β-binding protein expressed in vascular smooth muscle cells, modulates the arterial response to injury in vivo
Vasorin, a transforming growth factor β-binding protein expressed in vascular smooth muscle cells, modulates the arterial response to injury in vivo
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DOI：
10.1073/pnas.0404117101
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发表时间：
2004-07-20
影响因子：
11.1
通讯作者：
Kitamura, T
中科院分区：
文献类型：
--
作者：
Ikeda, Y;Imai, Y;Kitamura, T
生长因子、细胞表面受体、粘附分子和细胞外基质蛋白通过影响血管细胞的生长、迁移、分化和存活而在血管病理生理学中发挥关键作用。为了寻找心血管系统中分泌的和细胞表面表达的分子，我们通过使用逆转录病毒介导的信号序列捕获方法，分离了一种称为血管素的细胞表面蛋白。Vasorin是一种典型的I型膜蛋白，在细胞外结构域含有特征性富含亮氨酸的重复基序、表皮生长因子样基序和III型纤连蛋白样基序的串联阵列。表达分析表明，vasorin主要在血管平滑肌细胞中表达，并且其表达受发育调节。为了阐明vasorin的生物学功能，我们寻找了它的结合伴侣，发现vasorin在体外直接结合转化生长因子（TGF）-β并减弱TGF-β信号传导。在动脉损伤后的血管修复过程中，Vasorin表达下调，并且通过使用腺病毒介导的体内基因转移逆转vasorin下调，至少部分地通过抑制体内TGF-β信号传导显著减少损伤诱导的血管病变形成。这些结果表明，血管收缩素表达的下调有助于血管损伤后新生内膜的形成，并且血管收缩素调节血管壁中细胞对病理刺激的反应。因此，血管紧张素是血管纤维增生性疾病的潜在治疗靶点。
Growth factors, cell-surface receptors, adhesion molecules, and extracellular matrix proteins play critical roles in vascular pathophysiology by affecting growth, migration, differentiation, and survival of vascular cells. In a search for secreted and cell-surface molecules expressed in the cardiovascular system, by using a retrovirus-mediated signal sequence trap method, we isolated a cell-surface protein named vasorin. Vasorin is a typical type I membrane protein, containing tandem arrays of a characteristic leucine-rich repeat motif, an epidermal growth factor-like motif, and a fibronectin type III-like motif at the extracellular domain. Expression analyses demonstrated that vasorin is predominantly expressed in vascular smooth muscle cells, and that its expression is developmentally regulated. To clarify biological functions of vasorin, we searched for its binding partners and found that vasorin directly binds to transforming growth factor (TGF)-beta and attenuates TGF-beta signaling in vitro. Vasorin expression was down-regulated during vessel repair after arterial injury, and reversal of vasorin down-regulation, by using adenovirus-mediated in vivo gene transfer, significantly diminished injury-induced vascular lesion formation, at least in part, by inhibiting TGF-beta signaling in vivo. These results suggest that down-regulation of vasorin expression contributes to neointimal formation after vascular injury and that vasorin modulates cellular responses to pathological stimuli in the vessel wall. Thus, vasorin is a potential therapeutic target for vascular fibroproliferative disorders.