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

Abstract

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.

• Authors: Liping Tang, Bao Luo, Rakesh P Patel, Yiqun Ling, Junlan Zhang, Michael B Fallon
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 292 Issue 6 Pg. L1467-72 (Jun 2007) ISSN: 1040-0605 [Print] United States
• PMID: 17337507 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Endothelin-1
• Receptor, Endothelin B
• Nitric Oxide Synthase Type III
• Proto-Oncogene Proteins c-akt
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Cells, Cultured
• Endothelial Cells (cytology, physiology)
• Endothelin-1 (pharmacology)
• Gene Expression (physiology)
• Hepatopulmonary Syndrome (metabolism, physiopathology)
• Lung (blood supply)
• Microcirculation (physiology)
• Nitric Oxide Synthase Type III (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Receptor, Endothelin B (genetics, metabolism)
• Signal Transduction (drug effects, physiology)
• Stress, Mechanical