ADAM8 is a negative regulator of retinal neovascularization and of the growth of heterotopically injected tumor cells in mice.
ADAM8 is a negative regulator of retinal neovascularization and of the growth of heterotopically injected tumor cells in mice.
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DOI：
10.1007/s00109-010-0591-8
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发表时间：
2010-05
影响因子：
4.7
通讯作者：
Blobel, Carl P.
中科院分区：
文献类型：
--
作者：
Guaiquil, Victor H.;Swendeman, Steven;Zhou, Wenhui;Guaiquil, Patricio;Weskamp, Gisela;Bartsch, Joerg W.;Blobel, Carl P.
关键词：
ADAM 8是膜锚定金属蛋白酶“解整合素和金属蛋白酶”（ADAM）家族的成员。ADAM 8缺陷小鼠没有明显的自发性发育或病理缺陷，目前对ADAM 8在疾病中的作用知之甚少。在这里，我们研究了ADAM 8的贡献，病理新生血管形成的小鼠使用氧诱导的视网膜病变（OIR）模型和异位注射肿瘤细胞。我们发现，与野生型对照组相比，OIR模型中视网膜血管重建增加，但新生血管簇较少，Adam 8 −/−小鼠异位注射肿瘤细胞的生长增加。这些结果表明，在野生型小鼠中，ADAM 8的功能限制了这两个过程。在基于细胞的试验中，过表达ADAM 8增加了几种在血管生成中起作用的共表达膜蛋白（CD 31、Tie-2、Flk-1、Flt-1、EphrinB 2、EphB 4、VE-钙粘蛋白、KL-1、E-选择素和神经调节蛋白-1 β2）的胞外域脱落。因此，体内内皮细胞中ADAM 8的表达失调可能会增加这些和其他底物蛋白的加工。总之，我们的研究结果表明，抑制ADAM 8可能有助于促进血管再生，从而防止增生性视网膜病变中新生血管簇的形成。另一方面，在快速生长的肿瘤中，阻断ADAM 8可能是有害的。
ADAM8 is a member of the “a disintegrin and metalloproteinase” (ADAM) family of membrane-anchored metalloproteinases. ADAM8-deficient mice have no evident spontaneous developmental or pathological defects, and little is currently known about the role of ADAM8 in disease. Here, we investigated the contribution of ADAM8 to pathological neovascularization in mice using an oxygen-induced retinopathy (OIR) model and heterotopical injection of tumor cells. We found an increase in retinal re-vascularization but fewer neovascular tufts in the OIR model and increased growth of heterotopically injected tumor cells in Adam8−/− mice compared with wild-type controls. These results suggest that ADAM8 functions to limit both of these processes in wild-type mice. In cell-based assays, overexpression of ADAM8 increased the ectodomain shedding of several co-expressed membrane proteins with roles in angiogenesis (CD31, Tie-2, Flk-1, Flt-1, EphrinB2, EphB4, VE-cadherin, KL-1, E-selectin, and neuregulin-1β2). Thus, dysregulated expression of ADAM8 in endothelial cells in vivo could potentially increase the processing of these and other substrate proteins. Taken together, our findings suggest that inhibiting ADAM8 could be useful for promoting re-vascularization and thereby preventing formation of neovascular tufts in proliferative retinopathies. On the other hand, blocking ADAM8 could be detrimental in the context of rapidly growing tumors.
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影响因子：
9.8
作者：
Chen, Jing;Smith, Lois E. H.
通讯作者：
Smith, Lois E. H.
DOI：
10.1165/rcmb.2004-0026oc
发表时间：
2004-09-01
影响因子：
6.4
作者：
King, NE;Zimmermann, N;Rothenberg, ME
通讯作者：
Rothenberg, ME
影响因子：
9.8
作者：
Bradley, John;Ju, Meihua;Robinson, Gregory S.
通讯作者：
Robinson, Gregory S.
影响因子：
4.4
作者：
Gomez-Gaviro, Maria;Dominguez-Luis, Maria;Diaz-Gonzalez, Federico
通讯作者：
Diaz-Gonzalez, Federico
影响因子：
9.8
作者：
Sherris, David
通讯作者：
Sherris, David