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.
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.
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