title: Autotaxin/lysopholipase D and lysophosphatidic acid regulate murine hemostasis and thrombosis.
abstract: The lipid mediator lysophosphatidic acid (LPA) is a potent regulator of vascular cell function in vitro, but its physiologic role in the cardiovasculature is largely unexplored. To address the role of LPA in regulating platelet function and thrombosis, we investigated the effects of LPA on isolated murine platelets. Although LPA activates platelets from the majority of human donors, we found that treatment of isolated murine platelets with physiologic concentrations of LPA attenuated agonist-induced aggregation. Transgenic overexpression of autotaxin/lysophospholipase D (Enpp2), the enzyme necessary for production of the bulk of biologically active LPA in plasma, elevated circulating LPA levels and induced a bleeding diathesis and attenuation of thrombosis in mice. Intravascular administration of exogenous LPA recapitulated the prolonged bleeding time observed in Enpp2-Tg mice. Enpp2+/- mice, which have approximately 50% normal plasma LPA levels, were more prone to thrombosis. Plasma autotaxin associated with platelets during aggregation and concentrated in arterial thrombus, and activated but not resting platelets bound recombinant autotaxin/lysoPLD in an integrin-dependent manner. These results identify a novel pathway in which LPA production by autotaxin/lysoPLD regulates murine hemostasis and thrombosis and suggest that binding of autotaxin/lysoPLD to activated platelets may provide a mechanism to localize LPA production.
authors.affiliation: Division of Cardiovascular Medicine, The Gill Heart Institute, Lexington, Kentucky 40536-0200, USA.
authors.forename: Zehra
authors.initials: Z
authors.lastname: Pamuklar
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Federico
authors.forename: Shuying
authors.initials: S
authors.lastname: Liu
authors.forename: Makiko
authors.initials: M
authors.lastname: Umezu-Goto
authors.forename: Anping
authors.initials: A
authors.lastname: Dong
authors.forename: Manikandan
authors.initials: M
authors.lastname: Panchatcharam
authors.forename: Zachary
authors.initials: Z
authors.lastname: Fulkerson
authors.forename: Zachary
authors.initials: Z
authors.lastname: Fulerson
authors.forename: Evgeny
authors.initials: E
authors.lastname: Berdyshev
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.forename: Xianjun
authors.initials: X
authors.lastname: Fang
authors.forename: Laurens A
authors.initials: LA
authors.lastname: van Meeteren
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Moolenaar
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.forename: Susan S
authors.initials: SS
authors.lastname: Smyth
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D006470:Hemorrhage / Q000097:blood / Q000235:genetics; D006487:Hemostasis; D006801:Humans; D008246:Lysophospholipids / Q000097:blood* / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000097:blood* / Q000235:genetics; D043264:Phosphodiesterase I / Q000097:blood* / Q000235:genetics; D010727:Phosphoric Diester Hydrolases / Q000097:blood* / Q000235:genetics; D010974:Platelet Aggregation / Q000235:genetics; D011755:Pyrophosphatases / Q000097:blood* / Q000235:genetics; D013927:Thrombosis / Q000097:blood* / Q000235:genetics; D000099189:Lysophospholipase D
chemical_list: D008246:Lysophospholipids; D009097:Multienzyme Complexes; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid