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The Function of Endothelial TRPV4 Channels Is Attenuated in Pulmonary Arterial Hypertension
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A3737 - The Function of Endothelial TRPV4 Channels Is Attenuated in Pulmonary Arterial Hypertension
Author Block: C. Marziano, K. Hong, E. L. Cope, S. K. Sonkusare; Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, United States.
Rationale: The endothelium is an important regulator of pulmonary vascular resistance. Endothelial dysfunction is a major contributor to increased pulmonary vasoconstriction and elevated pulmonary arterial pressure (PAP) in pulmonary arterial hypertension (PAH). We recently identified TRPV4 (transient receptor potential vanilloid 4) channels as an important Ca2+ entry pathway in the intact endothelium from small, resistance-sized PAs, and demonstrated that TRPV4 channels regulate the activity of endothelial nitric oxide synthase (eNOS) and endothelium-dependent vasodilation of small PAs. NO bioavailability is reduced in PAs from PAH patients and mouse models of PAH. However, the pathological mechanism for reduced NO bioavailability in PAH are not clear. We hypothesized that perturbations of endothelial TRPV4 channel function contribute to reduced NO bioavailability and loss of endothelium-dependent vasodilation in PAH.
Methods: Three-week chronic hypoxia (CH) and Sugen 5416 + CH models were used to induce PAH in mice. TRPV4 channel function was studied using novel “optical patch clamp” approach that uses high-speed Ca2+ imaging to record single TRPV4 channel function (“TRPV4 sparklets”) in the intact endothelium from small, resistance-sized PAs. Pressure myography in small PAs was used to investigate the functional consequence of TRPV4 channel activation. Right ventricular systolic pressure (RVSP) was measured as an indicator of PAP. DAF-FM diacetate was used to measure changes in NO in the intact artery.
Results: In the CH model of PAH, TRPV4-/- mice showed exacerbated increase in RVSP when compared to wild-type control mice, supporting the role of TRPV4 channels as important regulators of PAP. In arteries obtained from CH or Sugen 5416 + CH mice, endothelial TRPV4 sparklet activity was significantly reduced and TRPV4-mediated vasodilation was drastically lower compared to normoxic control mice. The expression of TRPV4 channels at mRNA level and TRPV4 immunofluorescence in the endothelium were not altered in PAs from CH or Sugen 5416 + CH models of PAH, suggesting altered TRPV4 channel regulation, not altered expression, in PAH. Moreover, TRPV4-induced NO release was impaired in the PAs from PAH mice.
Conclusion: Reduced TRPV4 channel function may contribute to decreased NO bioavailability and loss of endothelium-dependent vasodilation in PAH. Targeting the mechanisms that impair TRPV4 channel function in PAH may lead to novel therapeutic strategies.
Author Block: C. Marziano, K. Hong, E. L. Cope, S. K. Sonkusare; Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, United States.
Rationale: The endothelium is an important regulator of pulmonary vascular resistance. Endothelial dysfunction is a major contributor to increased pulmonary vasoconstriction and elevated pulmonary arterial pressure (PAP) in pulmonary arterial hypertension (PAH). We recently identified TRPV4 (transient receptor potential vanilloid 4) channels as an important Ca2+ entry pathway in the intact endothelium from small, resistance-sized PAs, and demonstrated that TRPV4 channels regulate the activity of endothelial nitric oxide synthase (eNOS) and endothelium-dependent vasodilation of small PAs. NO bioavailability is reduced in PAs from PAH patients and mouse models of PAH. However, the pathological mechanism for reduced NO bioavailability in PAH are not clear. We hypothesized that perturbations of endothelial TRPV4 channel function contribute to reduced NO bioavailability and loss of endothelium-dependent vasodilation in PAH.
Methods: Three-week chronic hypoxia (CH) and Sugen 5416 + CH models were used to induce PAH in mice. TRPV4 channel function was studied using novel “optical patch clamp” approach that uses high-speed Ca2+ imaging to record single TRPV4 channel function (“TRPV4 sparklets”) in the intact endothelium from small, resistance-sized PAs. Pressure myography in small PAs was used to investigate the functional consequence of TRPV4 channel activation. Right ventricular systolic pressure (RVSP) was measured as an indicator of PAP. DAF-FM diacetate was used to measure changes in NO in the intact artery.
Results: In the CH model of PAH, TRPV4-/- mice showed exacerbated increase in RVSP when compared to wild-type control mice, supporting the role of TRPV4 channels as important regulators of PAP. In arteries obtained from CH or Sugen 5416 + CH mice, endothelial TRPV4 sparklet activity was significantly reduced and TRPV4-mediated vasodilation was drastically lower compared to normoxic control mice. The expression of TRPV4 channels at mRNA level and TRPV4 immunofluorescence in the endothelium were not altered in PAs from CH or Sugen 5416 + CH models of PAH, suggesting altered TRPV4 channel regulation, not altered expression, in PAH. Moreover, TRPV4-induced NO release was impaired in the PAs from PAH mice.
Conclusion: Reduced TRPV4 channel function may contribute to decreased NO bioavailability and loss of endothelium-dependent vasodilation in PAH. Targeting the mechanisms that impair TRPV4 channel function in PAH may lead to novel therapeutic strategies.
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