Chronic hypoxia, as occurs in many pulmonary diseases, results in pulmonary hypertension, which is characterized by profound vascular remodeling, increase in vascular tone, and enhanced responsiveness to vasoconstrictors. These functional changes are related to major alterations in Ca2+ homeostasis and may involve multiple Ca2+ pathways in PASMCs. Transient receptor potential (TRP) gene superfamily encodes a large repertoire of non-selective ion channels with a wide-range of physiological functions. Many of them are expressed in PASMCs. We have previously shown that chronic hypoxia upregulates TRPC1 and TRPC6 expression and enhances both store- and receptor-operated Ca2+ entries in PASMCs;and store-operated Ca2+ entry is responsible for the elevated resting [Ca2+]i and basal vasomotor tone. Our preliminary studies show that the increase in pulmonary arterial pressure (Ppa) and right heart hypertrophy were blunted in hypoxic trpc1-/- mice, suggesting a major involvement of TRPC1 in hypoxic pulmonary hypertension. In addition, we found that the mechanosensitive TRPV4 is highly expressed in PAs;and is the only channel, among all members of TRPM and TRPV subfamilies, being up-regulated by chronic hypoxia. Its up-regulation is associated with enhanced stretch-activated Ca2+ influx in PASMCs and the development of myogenic tone in isolated microvessels. Moreover, development of pulmonary hypertension was significantly delayed and suppressed in trpv4-/- mice. Since mechanical stretch imposed by elevated Ppa has been implicated as a trigger for the development of pulmonary hypertension, TRPV4 may operate as a mechanosensitive pathway for signaling the processes. Enhanced Ca2+ influx through TRP channels in hypoxic PASMCs may contribute to vascular remodeling through activation of Ca2+ sensitive transcription factors. Recent studies show that the nuclear factors of activated T-cells (NFAT) are involved in gene regulation in pulmonary hypertension. Based on these findings, we propose that the enhanced Ca2+ influx through the store-operated TRPC1, the receptor- operated TRPC6, and the mechanosensitive TRPV4 in PASMCs play essential roles in the increased vascular tone, responsiveness to vasoconstrictors, as well as vascular remodeling in hypoxic pulmonary hypertension;in part through the activation of calcineurin/NFAT pathway. To test this hypothesis, we will apply a combination of state-of-the-art techniques including Ca2+ imaging, patch clamping, laser-scanning confocal microscopy, siRNA gene knockout, and isolated microvessels, in conjunction with TRP channel knockout mice to examine (1) the roles and contributions of TRPC1 and TRPC6 to the vascular pathology in hypoxic pulmonary hypertension;(2) the functions of TRPV4 and its contribution to the development of hypoxic pulmonary hypertension;and (3) the interactions of calcineurin/NFAT pathways and TRP channels in hypoxic pulmonary hypertension. This project will provide unique information on the roles of TRP channel mediated Ca2+ signaling in chronic hypoxia-induce pulmonary hypertension.

Public Health Relevance

The development of pulmonary hypertension considerably worsens the prognosis for patients of many lung diseases, e.g. chronic obstructive airway disease, by causing right heart hypertrophy and failure. The proposed project will elucidate at the molecular and cellular level, the roles of several important TRP cation channels in the alteration of [Ca2+]i, vasomotor tone, and vascular remodeling in chronic hypoxia. The information generated by the proposed experiments may help to develop new treatments for pulmonary hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Moore, Timothy M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Lee, Suengwon; Paudel, Omkar; Jiang, Yongliang et al. (2015) CD38 mediates angiotensin II-induced intracellular Ca(2+) release in rat pulmonary arterial smooth muscle cells. Am J Respir Cell Mol Biol 52:332-41
Huang, Chun; Hu, Jinxing; Subedi, Krishna P et al. (2015) Extracellular Adenosine Diphosphate Ribose Mobilizes Intracellular Ca2+ via Purinergic-Dependent Ca2+ Pathways in Rat Pulmonary Artery Smooth Muscle Cells. Cell Physiol Biochem 37:2043-59
Xia, Yang; Yang, Xiao-Ru; Fu, Zhenzhen et al. (2014) Classical transient receptor potential 1 and 6 contribute to hypoxic pulmonary hypertension through differential regulation of pulmonary vascular functions. Hypertension 63:173-80
Subedi, Krishna P; Paudel, Omkar; Sham, James S K (2014) Detection of differentially regulated subsarcolemmal calcium signals activated by vasoactive agonists in rat pulmonary artery smooth muscle cells. Am J Physiol Cell Physiol 306:C659-69
Jiang, Yong-Liang; Lin, Amanda H Y; Xia, Yang et al. (2013) Nicotinic acid adenine dinucleotide phosphate (NAADP) activates global and heterogeneous local Ca2+ signals from NAADP- and ryanodine receptor-gated Ca2+ stores in pulmonary arterial myocytes. J Biol Chem 288:10381-94
Xia, Yang; Fu, Zhenzhen; Hu, Jinxing et al. (2013) TRPV4 channel contributes to serotonin-induced pulmonary vasoconstriction and the enhanced vascular reactivity in chronic hypoxic pulmonary hypertension. Am J Physiol Cell Physiol 305:C704-15
Liu, Xiao-Ru; Liu, Qing; Chen, Gai-Ying et al. (2013) Down-regulation of TRPM8 in pulmonary arteries of pulmonary hypertensive rats. Cell Physiol Biochem 31:892-904
Sun, Hui; Xia, Yang; Paudel, Omkar et al. (2012) Chronic hypoxia-induced upregulation of Ca2+-activated Cl- channel in pulmonary arterial myocytes: a mechanism contributing to enhanced vasoreactivity. J Physiol 590:3507-21
Yang, Xiao-Ru; Lin, Amanda H Y; Hughes, Jennifer M et al. (2012) Upregulation of osmo-mechanosensitive TRPV4 channel facilitates chronic hypoxia-induced myogenic tone and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 302:L555-68
Liu, Xiao-Ru; Zhang, Ming-Fang; Yang, Na et al. (2012) Enhanced store-operated Caýý+ entry and TRPC channel expression in pulmonary arteries of monocrotaline-induced pulmonary hypertensive rats. Am J Physiol Cell Physiol 302:C77-87

Showing the most recent 10 out of 19 publications