Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid
Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid
复制标题
DOI：
10.1074/jbc.m605142200
复制
发表时间：
2006-09-01
影响因子：
4.8
通讯作者：
Arai, Hiroyuki
中科院分区：
文献类型：
--
作者：
Tanaka, Masayuki;Okudaira, Shinichi;Arai, Hiroyuki
自分泌运动因子 (ATX) 是一种与癌症相关的运动原，通过产生生物活性小脂质溶血磷脂酸 (LPA)，在体外具有多种生物活性。 ATX 和 LPA 大量存在于循环血液中。然而，它们在流通中的作用仍有待解决。为了揭示 ATX 的生理作用，我们分析了 ATX 基因敲除小鼠。在ATX缺失的胚胎中，早期血管似乎正常形成，但它们未能发育成成熟血管。结果，ATX 缺失小鼠在胚胎第 10.5 天左右就会死亡。其表型比目前报道的LPA受体敲除小鼠严重得多。在培养的尿囊外植体中，ATX 和 LPA 均不产生血管生成。然而，它们都通过防止未被 LPA 受体拮抗剂 Ki16425 拮抗的血管解体来帮助维持预先形成的血管。在杂合小鼠的血清中，溶血磷脂酶 D 活性和 LPA 水平约为野生型小鼠的一半，表明 ATX 负责血清中大部分 LPA 的产生。本研究揭示了 ATX 在通过新的 LPA 信号通路稳定血管方面的先前未指定的作用。
Autotaxin (ATX) is a cancer-associated motogen that has multiple biological activities in vitro through the production of bioactive small lipids, lysophosphatidic acid (LPA). ATX and LPA are abundantly present in circulating blood. However, their roles in circulation remain to be solved. To uncover the physiological role of ATX we analyzed ATX knock-out mice. In ATX-null embryos, early blood vessels appeared to form properly, but they failed to develop into mature vessels. As a result ATX-null mice are lethal around embryonic day 10.5. The phenotype is much more severe than those of LPA receptor knock-out mice reported so far. In cultured allantois explants, neither ATX nor LPA was angiogenic. However, both of them helped to maintain preformed vessels by preventing disassembly of the vessels that was not antagonized by Ki16425, an LPA receptor antagonist. In serum from heterozygous mice both lysophospholipase D activity and LPA level were about half of those from wild-type mice, showing that ATX is responsible for the bulk of LPA production in serum. The present study revealed a previously unassigned role of ATX in stabilizing vessels through novel LPA signaling pathways.