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Peroxynitrite Impairs Caveolin‐1‐TRPV4 Channel Signaling in Pulmonary Hypertension
Author(s) -
Marziano Corina,
Hong Kwangseok,
Cope Eric L,
Ottolini Matteo,
Sonkusare Swapnil K
Publication year - 2019
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.2019.33.1_supplement.682.7
Subject(s) - trpv4 , transient receptor potential channel , vasodilation , endothelium , caveolin 1 , endothelial dysfunction , medicine , chemistry , nitric oxide , endocrinology , pharmacology , receptor
The endothelium is an important regulator of vascular resistance and overall pulmonary arterial pressure (PAP). Endothelial dysfunction in small, resistance pulmonary arteries (PAs) leads to impaired vasodilation, increased PAP, and the development of pulmonary hypertension (PH). However, the mechanisms leading to endothelial dysfunction in PH remain unknown. We recently identified endothelial TRPV4 (transient receptor potential vanilloid 4‐TRPV4 EC ) channels as important regulators of endothelium‐dependent vasodilation in small PAs, and showed that localized Ca 2+ influx events through TRPV4 EC channels activate an endothelial nitric oxide (eNOS)‐dependent vasodilatory pathway. Furthermore, inducible endothelium‐specific TRPV4 knockout (TRPV4 EC −/− ) mice have impaired vasodilation and elevated PAP, revealing TRPV4 EC channels as critical regulators of resting PAP. However, the signaling pathways that regulate TRPV4 EC channels and how they may be impaired in PH remain unknown. Caveolin‐1 (Cav‐1 EC ) is an important structural protein that is known to associate with TRPV4 channels in cultured endothelial cells, and global Cav‐1 −/− mice were shown to have high PAP. We, therefore, hypothesized that impairment in Cav‐1 EC ‐TRPV4 EC signaling regulation contributes to endothelial dysfunction in PH. PH was induced using a three week‐chronic hypoxia (CH) model. TRPV4 EC channel function was studied using high‐speed Ca 2+ imaging, which records Ca 2+ influx events through TRPV4 EC channels (TRPV4 EC sparklets) in the intact endothelium of small PAs. Pressure myography in small PAs was used to determine the functional outcome of TRPV4 EC channel signaling. Right ventricular systolic pressure (RVSP) was measured as an indicator of PAP. In normal PAs, Cav‐1 EC anchoring of protein kinase C (PKC) increased TRPV4 EC sparklet activity and TRPV4 EC‐ ‐dependent vasodilation. However, in CH, decreased Cav‐1 EC ‐PKC localization resulted in impaired TRPV4 EC sparklet activity and endotheliumdependent vasodilation. Elevated peroxynitrite (PN) levels have been shown to contribute to the development of PH. PN levels, as indicated by nitrotyrosine staining, were elevated in PAs from CH mice. PN scavenger, FeTPPS, rescued TRPV4 EC sparklet activity and vasodilation in PAs obtained from CH mice. Furthermore, acute injection of FeTPPS significantly lowered PAP in CH mice. Exogenous PN significantly decreased TRPV4 EC sparklet activity and vasodilation in control mice but had no effect on PAs from inducible Cav‐1 EC −/− mice, indicating that the effect of PN on TRPV4 EC channel activity is Cav‐1 EC ‐dependent. Our results support the idea that elevated PN levels in PH impairs Cav‐1 EC ‐PKC‐dependent potentiation of TRPV4 EC channel activity. Inhibition of TRPV4 EC channel activity by PN contributes to impaired vasodilation and elevated PAP observed in PH. Support or Funding Information 17PRE33660762, HL138496 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .