Corneal avascularity is due to soluble VEGF receptor-1.
Corneal avascularity is due to soluble VEGF receptor-1.
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DOI：
10.1038/nature05249
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发表时间：
2006-10-26
期刊：
影响因子：
64.8
通讯作者：
Ambati, Jayakrishna
中科院分区：
文献类型：
--
作者：
Ambati, Balamurali K.;Nozaki, Miho;Singh, Nirbhai;Takeda, Atsunobu;Jani, Pooja D.;Suthar, Tushar;Albuquerque, Romulo J. C.;Richter, Elizabeth;Sakurai, Eiji;Newcomb, Michael T.;Kleinman, Mark E.;Caldwell, Ruth B.;Lin, Qing;Ogura, Yuichiro;Orecchia, Angela;Samuelson, Don A.;Agnew, Dalen W.;St. Leger, Judy;Green, W. Richard;Mahasreshti, Parameshwar J.;Curiel, David T.;Kwan, Donna;Marsh, Helene;Ikeda, Sakae;Leiper, Lucy J.;Collinson, J. Martin;Bogdanovich, Sasha;Khurana, Tejvir S.;Shibuya, Masabumi;Baldwin, Megan E.;Ferrara, Napoleone;Gerber, Hans-Peter;De Falco, Sandro;Witta, Jassir;Baffi, Judit Z.;Raisler, Brian J.;Ambati, Jayakrishna
角膜血管的缺乏是光学清晰度和最佳视力所必需的，并且导致角膜被广泛用于验证许多疾病的促血管生成和抗血管生成治疗策略。但是，到目前为止，无血管表型的分子基础仍然不清楚，并且考虑到角膜中血管内皮生长因子(VEGF)-A（一种有效的血管生成刺激物）的存在以及角膜与血管化组织的接近，这一点更加值得注意。在这里，我们发现角膜表达可溶性VEGF受体-1 (sVEGFR-1，也称为sflt-1)，并且通过中和抗体、RNA干扰或cre -lox介导的基因破坏来抑制这种内源性VEGF- a陷阱，可以消除小鼠角膜无血管。角膜n1和Pax6+/−小鼠自发血管化的角膜以及无虹膜Pax6+/−患者缺乏sflt-1，重组sflt-1给药可恢复角膜n1和Pax6+/−小鼠的角膜血管。海牛是唯一已知的具有血管化角膜的生物，它不表达sflt-1，而儒艮（也是海牛目的成员）、大象（海牛现存最接近的陆地系统发育亲戚）和其他海洋哺乳动物（海豚和鲸鱼）的无血管角膜则含有sflt-1，这表明它具有至关重要的、进化上保守的作用。认识到sflt-1对于保存角膜的无血管范围至关重要，可以合理地指导其作为血管生成调节剂的平台，支持其在治疗新血管疾病中的应用，并可能为角膜的免疫特权提供见解。
Corneal avascularity—the absence of blood vessels in the cornea—is required for optical clarity and optimal vision, and has led to the cornea being widely used for validating pro- and anti-angiogenic therapeutic strategies for many disorders. But the molecular underpinnings of the avascular phenotype have until now remained obscure and are all the more remarkable given the presence in the cornea of vascular endothelial growth factor (VEGF)-A, a potent stimulator of angiogenesis, and the proximity of the cornea to vascularized tissues. Here we show that the cornea expresses soluble VEGF receptor-1 (sVEGFR-1; also known as sflt-1) and that suppression of this endogenous VEGF-A trap by neutralizing antibodies, RNA interference or Cre-lox-mediated gene disruption abolishes corneal avascularity in mice. The spontaneously vascularized corneas of corn1 and Pax6+/− mice and Pax6+/− patients with aniridia are deficient in sflt-1, and recombinant sflt-1 administration restores corneal avascularity in corn1 and Pax6+/− mice. Manatees, the only known creatures uniformly to have vascularized corneas, do not express sflt-1, whereas the avascular corneas of dugongs, also members of the order Sirenia, elephants, the closest extant terrestrial phylogenetic relatives of manatees, and other marine mammals (dolphins and whales) contain sflt-1, indicating that it has a crucial, evolutionarily conserved role. The recognition that sflt-1 is essential for preserving the avascular ambit of the cornea can rationally guide its use as a platform for angiogenic modulators, supports its use in treating neovascular diseases, and might provide insight into the immunological privilege of the cornea.
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