Abstract 13943: Endothelial-Targeted Hypoxia-Inducible Factor-1β (Hif-1β) Loss-of Function Alleviates the Monocrotaline-Induced Pulmonary Hypertension in Mice.
Introduction: Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteries that is characterized by a primary failure of the endothelial function, coupled with dysregulated cellular proliferation. Mice heterozygous for a knockout allele at the locus encoding HIFs are resistant to the development of PAH that is observed in their wild-type littermates. However, how the ubiquitously expressed HIFs are involved in this disease is still unclear. HIFs are known to mediate multiple pathogenic responses of pulmonary artery. We assessed the hypothesis that activation of HIFs in endothelial cells (ECs) leads to PAH by initiating dysfunctions of ECs.
Methods: Monocrotaline (MCT, 80 mg/kg body weight) was administrated to heterozygous mice lacking HIF-1β gene specifically in ECs, and PAH was induced 4 weeks later. The MCT-induced PAH in the mice was evaluated by measurement of the weight ratio of right ventricular to left ventricular with the septum, the number of small pulmonary arteries (<100 μm of diameter), and the indices of medial thickness of pulmonary arteries.
Results: MCT-induced pulmonary arteries demonstrated binding of pimonidazole, a hypoxia detection agent that binds to regions of hypoxia in the region around vascular walls including lung epithelial cells. Indices of the PAH were significantly alleviated in the Hif-1β+/− mice compared to the control as the following data showed; the weight ratio of right ventricular to left ventricular with septum was significantly decreased, 23.4±2.5% versus 29.2±3.2% the number of pulmonary arteries was significantly increased, 26.9±6.0/field versus 17.5±6.5/field; indices of the medial thickness was significantly decreased, 12.2±4.5% versus 23.7±5.9%, respectively p<0.05. The number of musculized pulmonary arteries (< 40 μm of diameter) in MCT-treated Hif-1β+/− mice was significantly decreased compared to that of the control mice. In addition, interestingly, the PAH in wild type mice was ameliorated by administration of bosentan, an endothelin receptor blocker, to the same level of that in Hif-1β+/− mice.
Conclusions: These results indicate that the development of MCT-induced PAH was mediated by HIF-1β in endothelial cells.
- © 2010 by American Heart Association, Inc.