The Mechanosensitive Ion Channel TRPV4 is a Regulator of Lung Development and Pulmonary Vasculature Stabilization

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Abstract

<div class="section"> <a class="named-anchor" id="d1060880e173">  </a> <h5 class="section-title" id="d1060880e174">Introduction</h5> <p id="Par1">Clinical observations and animal models suggest a critical role for the dynamic regulation of transmural pressure and peristaltic airway smooth muscle contractions for proper lung development. However, it is currently unclear how such mechanical signals are transduced into molecular and transcriptional changes at the cell level. To connect these physical findings to a mechanotransduction mechanism, we identified a known mechanosensor, TRPV4, as a component of this pathway. </p> </div><div class="section"> <a class="named-anchor" id="d1060880e178">  </a> <h5 class="section-title" id="d1060880e179">Methods</h5> <p id="Par2">Embryonic mouse lung explants were cultured on membranes and in submersion culture to modulate explant transmural pressure. Time-lapse imaging was used to capture active changes in lung biology, and whole-mount images were used to visualize the organization of the epithelial, smooth muscle, and vascular compartments. TRPV4 activity was modulated by pharmacological agonism and inhibition. </p> </div><div class="section"> <a class="named-anchor" id="d1060880e183">  </a> <h5 class="section-title" id="d1060880e184">Results</h5> <p id="Par3">TRPV4 expression is present in the murine lung with strong localization to the epithelium and major pulmonary blood vessels. TRPV4 agonism and inhibition resulted in hyper- and hypoplastic airway branching, smooth muscle differentiation, and lung growth, respectively. Smooth muscle contractions also doubled in frequency with agonism and were reduced by 60% with inhibition demonstrating a functional role consistent with levels of smooth muscle differentiation. Activation of TRPV4 increased the vascular capillary density around the distal airways, and inhibition resulted in a near complete loss of the vasculature. </p> </div><div class="section"> <a class="named-anchor" id="d1060880e188">  </a> <h5 class="section-title" id="d1060880e189">Conclusions</h5> <p id="Par4">These studies have identified TRPV4 as a potential mechanosensor involved in transducing mechanical forces on the airways to molecular and transcriptional events that regulate the morphogenesis of the three essential tissue compartments in the lung. <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/1a041316-48c3-456f-8c9f-a3dd6a68a2e0/PubMedCentral/image/12195_2018_538_Figa_HTML"/> </div> </p> </div><div class="section"> <a class="named-anchor" id="d1060880e195">  </a> <h5 class="section-title" id="d1060880e196">Electronic supplementary material</h5> <p id="d1060880e198">The online version of this article (10.1007/s12195-018-0538-7) contains supplementary material, which is available to authorized users. </p> </div>

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An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry.

Raymond Benza, Dave Miller, Robyn Barst … (2012)

The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry) was established to characterize the clinical course, treatment, and predictors of outcomes in patients with pulmonary arterial hypertension (PAH) in the United States. To date, estimated survival based on time of patient enrollment has been established and reported. To determine whether the survival of patients with PAH has improved over recent decades, we assessed survival from time of diagnosis for the REVEAL Registry cohort and compared these results to the estimated survival using the National Institutes of Health (NIH) prognostic equation. Newly or previously diagnosed patients (aged ≥ 3 months at diagnosis) with PAH enrolled from March 2006 to December 2009 at 55 US centers were included in the current analysis. A total of 2,635 patients qualified for this analysis. One-, 3-, 5-, and 7-year survival rates from time of diagnostic right-sided heart catheterization were 85%, 68%, 57%, and 49%, respectively. For patients with idiopathic/familial PAH, survival rates were 91% ± 2%, 74% ± 2%, 65% ± 3%, and 59% ± 3% compared with estimated survival rates of 68%, 47%, 36%, and 32%, respectively, using the NIH equation. Comprehensive analysis of survival from time of diagnosis in a large cohort of patients with PAH suggests considerable improvements in survival in the past 2 decades since the establishment of the NIH registry, the effects of which most likely reflect a combination of changes in treatments, improved patient support strategies, and possibly a PAH population at variance with other cohorts

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Edward Morrisey, Brigid L.M. Hogan (2010)

The mammalian respiratory system--the trachea and the lungs--arises from the anterior foregut through a sequence of morphogenetic events involving reciprocal endodermal-mesodermal interactions. The lung itself consists of two highly branched, tree-like systems--the airways and the vasculature--that develop in a coordinated way from the primary bud stage to the generation of millions of alveolar gas exchange units. We are beginning to understand some of the molecular and cellular mechanisms that underlie critical processes such as branching morphogenesis, vascular development, and the differentiation of multipotent progenitor populations. Nevertheless, many gaps remain in our knowledge, the filling of which is essential for understanding respiratory disorders, congenital defects in human neonates, and how the disruption of morphogenetic programs early in lung development can lead to deficiencies that persist throughout life. (c) 2010 Elsevier Inc. All rights reserved.

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Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era.

Ekta Khemani, Doff B McElhinney, Lawrence Rhein … (2007)

Although abnormal pulmonary vascular structure and function in preterm infants with bronchopulmonary dysplasia may predispose infants to pulmonary artery hypertension, little is known about the characteristics and outcomes of bronchopulmonary dysplasia-associated pulmonary artery hypertension in the surfactant era. We studied 42 premature infants ( or = 2 months after birth, between 1998 and 2006, at a median age of 4.8 months. Pulmonary artery hypertension was graded through echocardiography for all patients; 13 patients also underwent cardiac catheterization. Eighteen (43%) of 42 patients had severe pulmonary artery hypertension (systemic or suprasystemic right ventricular pressure). Among 13 patients who underwent catheterization, the mean pulmonary artery pressure was 43 +/- 8 mmHg and the pulmonary vascular resistance index was 9.9 +/- 2.8 Wood units. In 12 patients, pulmonary artery pressure and pulmonary vascular resistance improved with 100% oxygen and 80 ppm inhaled nitric oxide but remained elevated. The pulmonary vascular resistance index decreased to 7.9 +/- 3.8 Wood units in 100% oxygen and to 6.4 +/- 3.1 Wood units with the addition of nitric oxide. Sixteen patients (38%) died during the follow-up period. Estimated survival rates were 64% +/- 8% at 6 months and 53% +/- 11% at 2 years after diagnosis of pulmonary artery hypertension. In multivariate analyses, severe pulmonary artery hypertension and small birth weight for gestational age were associated with worse survival rates. Among 26 survivors (median follow-up period: 9.8 months), pulmonary artery hypertension was improved, relative to its most severe level, in 24 patients (89%). Premature infants with bronchopulmonary dysplasia and severe pulmonary artery hypertension are at high risk of death, particularly during the first 6 months after diagnosis of pulmonary artery hypertension.