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TRPV4 and TRPC1 Channels Mediate Hemodynamic Stress‐Induced Exacerbation of Pulmonary Hypertension
Author(s) -
Sham James S.K.,
Eldridge Lindsey,
Paudel Omkar,
Moldobaeva Aigul,
Wagner Elizabeth
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1016.23
Subject(s) - trpc1 , mechanosensitive channels , hemodynamics , medicine , transient receptor potential channel , pulmonary hypertension , vasoconstriction , vascular resistance , cardiology , trpv4 , hypoxic pulmonary vasoconstriction , endocrinology , receptor , ion channel
Pulmonary hypertension (PH) is a pathological condition associated with a wide spectrum of diseases with diverse etiologies. It is characterized by progressive pulmonary vascular remodeling, sustained vasoconstriction and enhanced vasoreactivity, resulting in elevated pulmonary vascular resistance and right heart failure. Recent studies suggest that increased hemodynamic stress/stretch in pulmonary vasculature plays important roles in vascular remodeling during the development of PH. However, the mechano‐transduction mechanism for hemodynamic stress in PH is unclear. Previous studies showed that several transient receptor potential (TRP) channels are mechanosensitive in different cell types. In particular, TRPV4, an osmo/mechanosensitive channel, is highly expressed in pulmonary endothelial and arterial smooth muscle cells (PASMCs). We have previously demonstrated that TRPV4 expression is upregulated in PASMCs during PH, and deletion of trpv4 gene delayed and suppressed PH development. Moreover, TRPV4 may form heterotetrameric channels with the store‐operated TRPC1, which is known to play crucial roles in PASMC proliferation and vascular remodeling. In this study, we sought to test the hypothesis that TRPV4 and TRPC1 are important components for mediating the signal of hemodynamic stress in vascular cells during PH. To test this hypothesis, left pulmonary arteries ligation (LPAL) was performed in WT, trpv4 −/− and trpc1 −/− mice to augment hemodynamic stress in pulmonary vasculature. After one week of recovery, LPAL and sham‐operated mice were exposed to normoxia, chronic hypoxia (CH, 3 week 10% O 2 ), or treated with weekly injections of Sugen‐5416 (20 mg/kg) and exposed to CH for 4 weeks. LPAL had no significant effect on the right ventricular systolic pressure (RVSP) and right ventricular mass index (RVMI, RV/(LV+S)) in normoxic mice, suggesting that the increase in pulmonary blood flow in the right lung is well compensated under control conditions. By contrast, the increase in RVSP and RVMI induced by CH exposure or sugen/hypoxia treatment were significantly enhanced in the LPAL‐operated WT mice compared to the sham‐control, indicating that the increased hemodynamic stress exacerbates PH. More importantly, the PH and RV hypertrophy caused by CH were significantly attenuated in the sham‐operated trpv4 −/− and trpc1 −/− mice, and LPAL in both types of knockout mice did not caused further increase in RVSP and RVMI. These results, hence, support our hypothesis that TRPV4 and TRPC1 channels play an essential role in mediating the hemodynamic stress‐induced alterations in vascular properties during PH; and they may be considered as novel targets for comprehensive treatment of PH. Support or Funding Information This work is supported in part by NIH grant HL075134