Abstract 520: Thromboxane Receptors in Smooth Muscle Promote Hypertension, Vascular Remodeling and Sudden Death

The prostanoid thromboxane (TxA2) is a potent vasoconstrictor and platelet aggregant that has been implicated in the pathogenesis of cardiovascular diseases including hypertension. Actions of thromboxane (TP) receptors in platelets and the vasculature have both been implicated in cardiovascular pathogenesis. To distinguish the contributions of vascular TP receptors in isolation, we generated mice with cell-specific deletion of TP receptors in smooth muscle cells (TP-SMKOs) using Cre/Loxp technology. We used the KISM22α-Cre transgenic mouse line, with Cre recombinase “knocked-in” to the Sm22α gene locus, to excise the conditional Tp receptor allele specifically in smooth muscle. mRNA for the TP-receptor was easily detected in aortae from control mice, but not from TP-SMKOs (P<0.005). Similarly, TP receptor mRNA expression in mesenteric arteries, with intact endothelium and adventitia, was decreased by ≈80% in TP-SMKOs (P=0.05). In TP-SMKOs, acute vasoconstrictor responses to the TP agonist U46619 were dramatically attenuated by ≈60% in both the peripheral and renal circulations (P<0.05), whereas acute vascular responses to angiotensin II were unaffected. Infusion of high-dose U46619 caused circulatory collapse and death in a majority of control mice, but TP-SMKOs were completely protected from U46619 -induced sudden death (P<0.05). Baseline blood pressures measured by radiotelemetry were similar in TP-SMKOs (111±1 mmHg) and Controls (114±1 mmHg; P=NS). However, the absence of TP receptors in vascular smooth muscle cells caused significant attenuation of angiotensin II-induced hypertension (controls: 159±2 mm Hg; TP-SMKO: 145±8 mm Hg, P<0.05) and diminished aortic medial hypertrophy in TP-SMKOs (59±4 μm) vs. Controls (79±7 μm; P<0.05). Thus, vascular TP receptors play a major role in shock, angiotensin II-induced hypertension, and vascular remodeling.