Thromboxane receptors in smooth muscle promote hypertension, vascular remodeling, and sudden death.

Published

Journal Article

The prostanoid thromboxane A2 has been implicated to contribute to the pathogenesis of many cardiovascular diseases, including hypertension. To study the role of vascular thromboxane-prostanoid (TP) receptors in blood pressure regulation, we generated mice with cell-specific deletion of TP receptors in smooth muscle using Cre/Loxp technology. We crossed the KISM22α-Cre transgenic mouse line expressing Cre recombinase in smooth muscle cells with a mouse line bearing a conditional allele of the Tbxa2r gene (Tp(flox)). In KISM22α-Cre(+)Tp(flox/flox) (TP-SMKO) mice, TP receptors were efficiently deleted from vascular smooth muscle cells. In TP-SMKOs, acute vasoconstrictor responses to the TP agonist U46619 were attenuated to a similar extent in both the peripheral and renal circulations. Yet, acute vascular responses to angiotensin II were unaffected at baseline and after chronic angiotensin II administration. Infusion of high-dose U46619 caused circulatory collapse and death in a majority of control mice but had negligible hemodynamic effects in TP-SMKOs, which were completely protected from U46619-induced sudden death. Baseline blood pressures were normal in TP-SMKOs. However, the absence of TP receptors in vascular smooth muscle cells was associated with significant attenuation of angiotensin II-induced hypertension and diminished vascular remodeling. This was also associated with reduced urinary thromboxane production after chronic angiotensin II. Thus, TP receptors in vascular smooth muscle cells play a major role in mediating the actions of thromboxane A(2) in TP agonist-induced shock, hypertension, and vascular remodeling of the aorta.

Full Text

Duke Authors

Cited Authors

  • Sparks, MA; Makhanova, NA; Griffiths, RC; Snouwaert, JN; Koller, BH; Coffman, TM

Published Date

  • January 2013

Published In

Volume / Issue

  • 61 / 1

Start / End Page

  • 166 - 173

PubMed ID

  • 23150508

Pubmed Central ID

  • 23150508

Electronic International Standard Serial Number (EISSN)

  • 1524-4563

Digital Object Identifier (DOI)

  • 10.1161/HYPERTENSIONAHA.112.193250

Language

  • eng

Conference Location

  • United States