title: Transient Receptor Potential Channel 4 Encodes a Vascular Permeability Defect and High-Frequency Ca(2+) Transients in Severe Pulmonary Arterial Hypertension.
abstract: The canonical transient receptor potential channel 4 (TRPC4) comprises an endothelial store-operated Ca(2+) entry channel, and TRPC4 inactivation confers a survival benefit in pulmonary arterial hypertension (PAH). Endothelial Ca(2+) signals mediated by TRPC4 enhance vascular permeability in vitro, but the contribution of TRPC4-dependent Ca(2+) signals to the regulation of endothelial permeability in PAH is poorly understood. We tested the hypothesis that TRPC4 increases vascular permeability and alters the frequency of endothelial Ca(2+) transients in PAH. We measured permeability in isolated lungs, and found that TRPC4 exaggerated permeability responses to thapsigargin in Sugen/hypoxia-treated PAH rats. We compared endothelial Ca(2+) activity of wild-type with TRPC4-knockout rats using confocal microscopy, and evaluated how Ca(2+) signals were influenced in response to thapsigargin and sequential treatment with acetylcholine. We found that thapsigargin-stimulated Ca(2+) signals were increased in PAH, and recovered by TRPC4 inactivation. Store depletion revealed bimodal Ca(2+) responses to acetylcholine, with both short- and long-duration populations. Our results show that TRPC4 underlies an exaggerated endothelial permeability response in PAH. Furthermore, TRPC4 increased the frequency of endothelial Ca(2+) transients in severe PAH, suggesting that TRPC4 provides a Ca(2+) source associated with endothelial dysfunction in the pathophysiology of PAH. This phenomenon represents a new facet of the etiology of PAH, and may contribute to PAH vasculopathy by enabling inflammatory mediator flux across the endothelial barrier.
authors.affiliation: Department of Physiology and Cell Biology, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama.
authors.forename: Michael
authors.initials: M
authors.lastname: Francis
authors.affiliation: Department of Physiology and Cell Biology, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama.
authors.forename: Ningyong
authors.initials: N
authors.lastname: Xu
authors.affiliation: Department of Physiology and Cell Biology, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama.
authors.forename: Chun
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Physiology and Cell Biology, University of South Alabama, Mobile, Alabama; Center for Lung Biology, University of South Alabama, Mobile, Alabama; Department of Medicine, University of South Alabama, Mobile, Alabama. Electronic address: tstevens@southalabama.edu.
authors.forename: Troy
authors.initials: T
authors.lastname: Stevens
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002199:Capillary Permeability / Q000235:genetics*; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000503:physiopathology*; D018613:Microscopy, Confocal; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000502:physiology*; D050052:TRPC Cation Channels / Q000378:metabolism*
chemical_list: D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; D002118:Calcium