Coagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A2.

Published

Journal Article

Thromboxane A2 (TXA2) is a labile metabolite of arachidonic acid that has potent biological effects. Its actions are mediated by G protein-coupled thromboxane-prostanoid (TP) receptors. TP receptors have been implicated in the pathogenesis of cardiovascular diseases. To investigate the physiological functions of TP receptors, we generated TP receptor-deficient mice by gene targeting. Tp-/- animals reproduce and survive in expected numbers, and their major organ systems are normal. Thromboxane agonist binding cannot be detected in tissues from Tp-/- mice. Bleeding times are prolonged in Tp-/- mice and their platelets do not aggregate after exposure to TXA2 agonists. Aggregation responses after collagen stimulation are also delayed, although ADP-stimulated aggregation is normal. Infusion of the TP receptor agonist U-46619 causes transient increases in blood pressure followed by cardiovascular collapse in wild-type mice, but U-46619 caused no hemodynamic effect in Tp-/- mice. Tp-/- mice are also resistant to arachidonic acid-induced shock, although arachidonic acid signifi-cantly reduced blood pressure in Tp-/- mice. In summary, Tp-/- mice have a mild bleeding disorder and altered vascular responses to TXA2 and arachidonic acid. Our studies suggest that most of the recognized functions of TXA2 are mediated by the single known Tp gene locus.

Full Text

Duke Authors

Cited Authors

  • Thomas, DW; Mannon, RB; Mannon, PJ; Latour, A; Oliver, JA; Hoffman, M; Smithies, O; Koller, BH; Coffman, TM

Published Date

  • December 1998

Published In

Volume / Issue

  • 102 / 11

Start / End Page

  • 1994 - 2001

PubMed ID

  • 9835625

Pubmed Central ID

  • 9835625

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

International Standard Serial Number (ISSN)

  • 0021-9738

Digital Object Identifier (DOI)

  • 10.1172/jci5116

Language

  • eng