Delayed Microvascular Shear Adaptation in Pulmonary Arterial Hypertension. Role of Platelet Endothelial Cell Adhesion Molecule-1 Cleavage.

Autor:	Szulcek R; 1 Department of Pulmonology.; 2 Department of Physiology., Happé CM; 1 Department of Pulmonology., Rol N; 1 Department of Pulmonology.; 2 Department of Physiology., Fontijn RD; 3 Department of Molecular Cell Biology and Immunology., Dickhoff C; 4 Department of Surgery, and., Hartemink KJ; 4 Department of Surgery, and., Grünberg K; 5 Department of Pathology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands., Tu L; 6 INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.; 7 Université Paris-Sud, School of Médecine, Le Kremlin-Bicêtre, Paris, France., Timens W; 8 Department of Pathology and Medical Biology, and., Nossent GD; 9 Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; and., Paul MA; 4 Department of Surgery, and., Leyen TA; 3 Department of Molecular Cell Biology and Immunology., Horrevoets AJ; 3 Department of Molecular Cell Biology and Immunology., de Man FS; 1 Department of Pulmonology., Guignabert C; 6 INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.; 7 Université Paris-Sud, School of Médecine, Le Kremlin-Bicêtre, Paris, France., Yu PB; 10 Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Vonk-Noordegraaf A; 1 Department of Pulmonology., van Nieuw Amerongen GP; 2 Department of Physiology., Bogaard HJ; 1 Department of Pulmonology.
Jazyk:	angličtina
Zdroj:	American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2016 Jun 15; Vol. 193 (12), pp. 1410-20.
DOI:	10.1164/rccm.201506-1231OC
Abstrakt:	Rationale: Altered pulmonary hemodynamics and fluid flow-induced high shear stress (HSS) are characteristic hallmarks in the pathogenesis of pulmonary arterial hypertension (PAH). However, the contribution of HSS to cellular and vascular alterations in PAH is unclear. Objectives: We hypothesize that failing shear adaptation is an essential part of the endothelial dysfunction in all forms of PAH and tested whether microvascular endothelial cells (MVECs) or pulmonary arterial endothelial cells (PAECs) from lungs of patients with PAH adapt to HSS and if the shear defect partakes in vascular remodeling in vivo. Methods: PAH MVEC (n = 7) and PAH PAEC (n = 3) morphology, function, protein, and gene expressions were compared with control MVEC (n = 8) under static culture conditions and after 24, 72, and 120 hours of HSS. Measurements and Main Results: PAH MVEC showed a significantly delayed morphological shear adaptation (P = 0.03) and evidence of cell injury at sites of nonuniform shear profiles that are critical loci for vascular remodeling in PAH. In clear contrast, PAEC isolated from the same PAH lungs showed no impairments. PAH MVEC gene expression and transcriptional shear activation were not altered but showed significant decreased protein levels (P = 0.02) and disturbed interendothelial localization of the shear sensor platelet endothelial cell adhesion molecule-1 (PECAM-1). The decreased PECAM-1 levels were caused by caspase-mediated cytoplasmic cleavage but not increased cell apoptosis. Caspase blockade stabilized PECAM-1 levels, restored endothelial shear responsiveness in vitro, and attenuated occlusive vascular remodeling in chronically hypoxic Sugen5416-treated rats modeling severe PAH. Conclusions: Delayed shear adaptation, which promotes shear-induced endothelial injury, is a newly identified dysfunction specific to the microvascular endothelium in PAH. The shear response is normalized on stabilization of PECAM-1, which reverses intimal remodeling in vivo.
Databáze:	MEDLINE
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