Endothelial HIF signaling regulates pulmonary fibrosis-associated pulmonary hypertension
| Autor: | Christa Gaskill, Ayub K. Karwandyar, Niki Penner, James West, Anna R. Hemnes, Erica J. Carrier, Christy Moore, Andrew Bryant, Thomas R. Blackwell, Melinda E. McConaha, William Lawson, Edward W. Scott, Santhi Gladson, Vasiliy V. Polosukhin, Volker H. Haase, Susan M. Majka, Joshua P. Fessel, Hui-Jia Dong, Timothy S. Blackwell, Megha Talati, Linda A. Gleaves, Sheila Shay, Ankita Burman, Ryan P. Carrick, Harikrishna Tanjore, Brittany R. Jones |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Pathology medicine.medical_specialty Physiology Hypertension Pulmonary Vascular permeability Mice Transgenic Biology Pulmonary Artery Vascular Remodeling Muscle Smooth Vascular 03 medical and health sciences Idiopathic pulmonary fibrosis Fibrosis Physiology (medical) Pulmonary fibrosis medicine Animals Hypoxia Cells Cultured Cell Proliferation Endothelial Cells Cell Biology Hypoxia (medical) medicine.disease Pulmonary hypertension Vascular endothelial growth factor B 030104 developmental biology Hypoxia-inducible factors Call for Papers Endothelium Vascular Hypoxia-Inducible Factor 1 medicine.symptom |
| Popis: | Pulmonary hypertension (PH) complicating chronic parenchymal lung disease, such as idiopathic pulmonary fibrosis, results in significant morbidity and mortality. Since the hypoxia-inducible factor (HIF) signaling pathway is important for development of pulmonary hypertension in chronic hypoxia, we investigated whether HIF signaling in vascular endothelium regulates development of PH related to pulmonary fibrosis. We generated a transgenic model in which HIF is deleted within vascular endothelial cells and then exposed these mice to chronic intraperitoneal bleomycin to induce PH associated with lung fibrosis. Although no differences in the degree of fibrotic remodeling were observed, we found that endothelial HIF-deficient mice were protected against development of PH, including right ventricle and pulmonary vessel remodeling. Similarly, endothelial HIF-deficient mice were protected from PH after a 4-wk exposure to normobaric hypoxia. In vitro studies of pulmonary vascular endothelial cells isolated from the HIF-targeted mice and controls revealed that endothelial HIF signaling increases endothelial cell expression of connective tissue growth factor, enhances vascular permeability, and promotes pulmonary artery smooth muscle cell proliferation and wound healing ability, all of which have the potential to impact the development of PH in vivo. Taken together, these studies demonstrate that vascular endothelial cell HIF signaling is necessary for development of hypoxia and pulmonary fibrosis associated PH. As such, HIF and HIF-regulated targets represent a therapeutic target in these conditions. |
| Databáze: | OpenAIRE |
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