Modulation of pulmonary endothelial endothelin B receptor expression and signaling: implications for experimental hepatopulmonary syndrome

1 Department of Internal Medicine and Liver Center and 2 Department of Pathology, University of Alabama at Birmingham, and 3 Birmingham Veterans Administration Medical Center, Birmingham, Alabama Submitted 10 November 2006 ; accepted in final form 22 February 2007 The hepatopulmonary syndrome (HPS) results from intrapulmonary vasodilation in the setting of cirrhosis and portal hypertension. In experimental HPS, pulmonary endothelial endothelin B (ET B ) receptor overexpression and increased circulating endothelin-1 (ET-1) contribute to vasodilation through enhanced endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) production. In both experimental cirrhosis and prehepatic portal hypertension, ET B receptor overexpression correlates with increased vascular shear stress, a known modulator of ET B receptor expression. We investigated the mechanisms of pulmonary endothelial ET B receptor-mediated eNOS activation by ET-1 in vitro and in vivo. The effect of shear stress on ET B receptor expression was assessed in rat pulmonary microvascular endothelial cells (RPMVECs). The consequences of ET B receptor overexpression on ET-1-dependent ET B receptor-mediated eNOS activation were evaluated in RPMVECs and in prehepatic portal hypertensive animals exposed to exogenous ET-1. Laminar shear stress increased ET B receptor expression in RPMVECs without altering mRNA stability. Both shear-mediated and targeted overexpression of the ET B receptor enhanced ET-1-mediated ET B receptor-dependent eNOS activation in RPMVECs through Ca 2+ -mediated signaling pathways and independent of Akt activation. In prehepatic portal hypertensive animals relative to control, ET-1 administration also activated eNOS independent of Akt activation and triggered HPS. These findings support that increased pulmonary microvascular endothelial ET B receptor expression modulates ET-1-mediated eNOS activation, independent of Akt, and contributes to the development of HPS. endothelial nitric oxide synthase; Akt; shear stress Address for reprint requests and other correspondence: M. B. Fallon, Univ. of Alabama at Birmingham, 290 MCLM, 1918 Univ. Blvd., Birmingham, AL 35294-0005 (e-mail: mfallon{at}uab.edu )