Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid.
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.
Tanaka
Masayuki
M
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Okudaira
Shinichi
S
Kishi
Yasuhiro
Y
Ohkawa
Ryunosuke
R
Iseki
Sachiko
S
Ota
Masato
M
Noji
Sumihare
S
Yatomi
Yutaka
Y
Aoki
Junken
J
Arai
Hiroyuki
H
D000818:Animals; D018507:Gene Expression Regulation, Developmental; D005821:Genetic Techniques; D006579:Heterozygote; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D009097:Multienzyme Complexes / Q000737:chemistry / Q000502:physiology*; D009389:Neovascularization, Pathologic; D010641:Phenotype; D043264:Phosphodiesterase I / Q000737:chemistry / Q000502:physiology*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism; D011755:Pyrophosphatases / Q000737:chemistry / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction; D013997:Time Factors; D000099189:Lysophospholipase D
D008246:Lysophospholipids; D009097:Multienzyme Complexes; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D011994:Recombinant Proteins; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid