Pulmonary hypertension is a severely debilitating disease with no cure. Morphometric studies revealed that the development of pulmonary hypertension is associated with structural remodeling of the small pulmonary arteries, characterized by thickening of the smooth muscle cell layer and extension of new muscle around previously non-muscular precapillary arterioles. While the former is thought to be due to pulmonary arterial smooth muscle cell (PASMC) hypertrophy, hyperplasia and resistance to apoptosis, the latter is believed to result from PASMC migration. Our laboratory identified a new candidate as a regulator of PASMC migration, proliferation and survival: aquaporins (AQPs). AQPs are a family of proteins that form transmembrane channels which facilitate the transport of water into and out of cells. We have evidence that aquaporin 1 (AQP1), the first family member identified, is expressed in PASMCs, induced by hypoxia and required for PASMC migration and proliferation. Moreover, we have generated exciting data indicating a critical role for the AQP1 C-terminal tail, but not water transport, in controlling these cellular processes. Our preliminary data also indicate that increased AQP1 protein is associated with elevated ?atenin expression, a protein that regulates migratory, proliferative and survival responses in PASMCs. How AQP1 regulates ?atenin levels is unknown, but we show that the AQP1 cytoplasmic tail is required. Finally, while we have strong evidence that AQP1 plays a critical role in mediating PASMC migration and proliferation, whether AQP1 contributes to the development of vascular remodeling and PH remains unknown. Thus, the goals of this study are to: 1) elucidate the mechanism by which hypoxia upregulates AQP1 in PASMCs; 2) identify the mechanism by which AQP1 modulates ?atenin expression and determine whether ?atenin is required for AQP1-mediated changes in cell function; and 3) determine whether AQP1 plays a role in facilitating pulmonary hypertension.

Public Health Relevance

The experiments in this proposal will explore cellular mechanisms involved in the development of hypoxia-induced and idiopathic pulmonary arterial hypertension (IPAH), a devastating disease with limited treatment options. In particular, we will explore the role of the water channel, aquaporin 1, in mediating cellular changes that occur in the pulmonary vasculature with development of pulmonary hypertension. Such information is crucial to advancing treatment and developing new therapeutic options to treat this deadly disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Xiao, Lei
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Shimoda, Larissa A (2018) Let's Talk about Sex: A Novel Mechanism by Which Estrogen Receptor ? Limits Hypoxia-Inducible Factor Expression in Pulmonary Endothelial Cells. Am J Respir Cell Mol Biol 59:11-12
Yun, Xin; Jiang, Haiyang; Lai, Ning et al. (2017) Aquaporin 1-mediated changes in pulmonary arterial smooth muscle cell migration and proliferation involve ?-catenin. Am J Physiol Lung Cell Mol Physiol 313:L889-L898
Semenza, Gregg L (2017) A compendium of proteins that interact with HIF-1?. Exp Cell Res 356:128-135
Suresh, Karthik; Shimoda, Larissa A (2016) Lung Circulation. Compr Physiol 6:897-943
Lai, Ning; Lade, Julie; Leggett, Kyle et al. (2014) The aquaporin 1 C-terminal tail is required for migration and growth of pulmonary arterial myocytes. Am J Respir Cell Mol Biol 50:1010-20