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

Abstract

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.

• Authors: Matthew A Sparks, Natalia A Makhanova, Robert C Griffiths, John N Snouwaert, Beverly H Koller, Thomas M Coffman
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 61 Issue 1 Pg. 166-73 (Jan 2013) ISSN: 1524-4563 [Electronic] United States
• PMID: 23150508 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Thromboxane
• Vasoconstrictor Agents
• Thromboxane A2
• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid

Topics

• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid (pharmacology)
• Animals
• Aorta (drug effects, metabolism)
• Blood Pressure (drug effects)
• Death, Sudden
• Hypertension (genetics, metabolism)
• Mice
• Mice, Knockout
• Muscle, Smooth, Vascular (drug effects, metabolism)
• Myocytes, Smooth Muscle (drug effects, metabolism)
• Receptors, Thromboxane (genetics, metabolism)
• Thromboxane A2 (pharmacology)
• Vasoconstriction (drug effects)
• Vasoconstrictor Agents (pharmacology)