Smooth Muscle Endothelin B Receptors Regulate Blood Pressure but Not Vascular Function or Neointimal Remodeling

The role of smooth muscle endothelin_B (ET_B) receptors in regulating vascular function, blood pressure (BP), and neointimal remodeling has not been established. Selective knockout mice were generated to address the hypothesis that loss of smooth muscle ET_B receptors would reduce BP, alter vascular contractility, and inhibit neointimal remodeling. ET_B receptors were selectively deleted from smooth muscle by crossing floxed ET_B mice with those expressing cre-recombinase controlled by the transgelin promoter. Functional consequences of ET_B deletion were assessed using myography. BP was measured by telemetry, and neointimal lesion formation induced by femoral artery injury. Lesion size and composition (day 28) were analyzed using optical projection tomography, histology, and immunohistochemistry. Selective deletion of ET_B was confirmed by genotyping, autoradiography, polymerase chain reaction, and immunohistochemistry. ET_B-mediated contraction was reduced in trachea, but abolished from mesenteric veins, of knockout mice. Induction of ET_B-mediated contraction in mesenteric arteries was also abolished in these mice. Femoral artery function was unaltered, and baseline BP modestly elevated in smooth muscle ET_B knockout compared with controls (+4.2±0.2 mm Hg; P<0.0001), but salt-induced and ET_B blockade-mediated hypertension were unaltered. Circulating endothelin-1 was not altered in knockout mice. ET_B-mediated contraction was not induced in femoral arteries by incubation in culture medium or lesion formation, and lesion size was not altered in smooth muscle ET_B knockout mice. In the absence of other pathology, ET_B receptors in vascular smooth muscle make a small but significant contribution to ET_B-dependent regulation of BP. These ET_B receptors have no effect on vascular contraction or neointimal remodeling.