title: Caveolae are involved in mechanotransduction during pulmonary hypertension.
abstract: Caveolae are stiff plasma membrane microdomains implicated in various cell response mechanisms like Ca(2+) signaling and mechanotransduction. Pulmonary arterial smooth muscle cells (PASMC) transduce mechanical stimuli into Ca(2+) increase via plasma membrane stretch-activated channels (SAC). This mechanotransduction process is modified in pulmonary hypertension (PH) during which stretch forces are increased by the increase in arterial blood pressure. We propose to investigate how caveolae are involved in the pathophysiology of PH and particularly in mechanotransduction. PASMC were freshly isolated from control rats (Ctrl rats) and rats suffering from PH induced by 3 wk of chronic hypoxia (CH rats). Using a caveolae disrupter (methyl-β-cyclodextrin), we showed that SAC activity measured by patch-clamp, stretch-induced Ca(2+) increase measured with indo-1 probe and pulmonary arterial ring contraction to osmotic shock are enhanced in Ctrl rats when caveolae are disrupted. In CH rats, SAC activity, Ca(2+), and contraction responses to stretch are all higher compared with Ctrl rats. However, in contrast to Ctrl rats, caveolae disruption in CH-PASMC, reduces SAC activity, Ca(2+) responses to stretch and arterial contractions. Furthermore, by means of immunostainings and transmission electron microscopy, we observed that caveolae and caveolin-1 are expressed in PASMC from both Ctrl and CH rats and localize close to subplasmalemmal sarcoplasmic reticulum (ryanodine receptors) and mitochondria, thus facilitating Ca(2+) exchanges, particularly in CH. In conclusion, caveolae are implicated in mechanotransduction in Ctrl PASMC by buffering mechanical forces. In PH-PASMC, caveolae form a distinct Ca(2+) store facilitating Ca(2+) coupling between SAC and sarcoplasmic reticulum.
authors.affiliation: Centre de Recherche Cardio-Thoracique de Bordeaux, Université de Bordeaux, Bordeaux, France; and Centre de Recherche Cardio-Thoracique de Bordeaux, INSERM U1045, Bordeaux, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Gilbert
authors.affiliation: Centre de Recherche Cardio-Thoracique de Bordeaux, Université de Bordeaux, Bordeaux, France; and Centre de Recherche Cardio-Thoracique de Bordeaux, INSERM U1045, Bordeaux, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ducret
authors.affiliation: Centre de Recherche Cardio-Thoracique de Bordeaux, Université de Bordeaux, Bordeaux, France; and Centre de Recherche Cardio-Thoracique de Bordeaux, INSERM U1045, Bordeaux, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Savineau
authors.affiliation: Centre de Recherche Cardio-Thoracique de Bordeaux, Université de Bordeaux, Bordeaux, France; and Centre de Recherche Cardio-Thoracique de Bordeaux, INSERM U1045, Bordeaux, France.
authors.forename: Roger
authors.initials: R
authors.lastname: Marthan
authors.affiliation: Centre de Recherche Cardio-Thoracique de Bordeaux, Université de Bordeaux, Bordeaux, France; and Centre de Recherche Cardio-Thoracique de Bordeaux, INSERM U1045, Bordeaux, France jean-francois.quignard@u-bordeaux.fr.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Quignard
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D021941:Caveolae / Q000502:physiology*; D051242:Caveolin 1 / Q000378:metabolism; D002478:Cells, Cultured; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology; D008297:Male; D040542:Mechanotransduction, Cellular; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D017208:Rats, Wistar
chemical_list: C495537:Cav1 protein, rat; D051242:Caveolin 1
keywords: calcium signaling; caveolae; pulmonary circulation; pulmonary hypertension; stretch activated channel