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

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.

[1]  C. Germer,et al.  Soluble VE-cadherin is involved in endothelial barrier breakdown in systemic inflammation and sepsis. , 2015, Cardiovascular research.

[2]  Pin-i Chen,et al.  BMPR2 preserves mitochondrial function and DNA during reoxygenation to promote endothelial cell survival and reverse pulmonary hypertension. , 2015, Cell metabolism.

[3]  Alys R. Clark,et al.  Dynamic blood flow and wall shear stress in pulmonary hypertensive disease , 2014, 2014 36th Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[4]  N. Voelkel,et al.  The role of vascular endothelial growth factor in pulmonary arterial hypertension. The angiogenesis paradox. , 2014, American journal of respiratory cell and molecular biology.

[5]  J. Privratsky,et al.  PECAM-1: regulator of endothelial junctional integrity , 2014, Cell and Tissue Research.

[6]  M. Humbert,et al.  Pathogenesis of pulmonary arterial hypertension: lessons from cancer , 2013, European Respiratory Review.

[7]  S. Erzurum,et al.  Nitrosation-Dependent Caveolin 1 Phosphorylation, Ubiquitination, and Degradation and its Association with Idiopathic Pulmonary Arterial Hypertension , 2013, Pulmonary circulation.

[8]  N. Westerhof,et al.  SuHx rat model: partly reversible pulmonary hypertension and progressive intima obstruction , 2013, European Respiratory Journal.

[9]  C. Daniels,et al.  Pulmonary Hypertension and Idiopathic Pulmonary Fibrosis: A Dastardly Duo , 2013, The American journal of the medical sciences.

[10]  R. Berger,et al.  The role of disturbed blood flow in the development of pulmonary arterial hypertension: lessons from preclinical animal models. , 2013, American journal of physiology. Lung cellular and molecular physiology.

[11]  Horst Olschewski,et al.  Updated clinical classification of pulmonary hypertension. , 2009, Journal of the American College of Cardiology.

[12]  M. Humbert,et al.  Copper dependence of angioproliferation in pulmonary arterial hypertension in rats and humans. , 2012, American journal of respiratory cell and molecular biology.

[13]  L. Farkas,et al.  New models of pulmonary hypertension based on VEGF receptor blockade-induced endothelial cell apoptosis , 2012, Pulmonary circulation.

[14]  N. Voelkel,et al.  Pathobiology of pulmonary arterial hypertension and right ventricular failure , 2012, European Respiratory Journal.

[15]  M. Paul,et al.  Opposing Effects of the Angiopoietins on the Thrombin-Induced Permeability of Human Pulmonary Microvascular Endothelial Cells , 2011, PloS one.

[16]  M. Humbert,et al.  Autocrine fibroblast growth factor-2 signaling contributes to altered endothelial phenotype in pulmonary hypertension. , 2011, American journal of respiratory cell and molecular biology.

[17]  J. Privratsky,et al.  Relative contribution of PECAM-1 adhesion and signaling to the maintenance of vascular integrity , 2011, Journal of Cell Science.

[18]  E. L. Ramirez,et al.  Shear stress preconditioning modulates endothelial susceptibility to circulating TNF-alpha and monocytic cell recruitment in a simplified model of arterial bifurcations. , 2009, Atherosclerosis.

[19]  N. Morrell,et al.  TGF-beta and BMPR-II pharmacology--implications for pulmonary vascular diseases. , 2009, Current opinion in pharmacology.

[20]  N. Voelkel,et al.  The cancer paradigm of severe pulmonary arterial hypertension. , 2008, American journal of respiratory and critical care medicine.

[21]  M. Rabinovitch.  Molecular pathogenesis of pulmonary arterial hypertension. , 2008, The Journal of clinical investigation.

[22]  W. Aird.  Endothelium in health and disease. , 2008, Pharmacological reports : PR.

[23]  S. Nourshargh,et al.  PECAM-1: a multi-functional molecule in inflammation and vascular biology. , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[24]  Katherine Holmes,et al.  Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. , 2007, Cellular signalling.

[25]  David Hecht,et al.  Oral IDN‐6556, an antiapoptotic caspase inhibitor, may lower aminotransferase activity in patients with chronic hepatitis C , 2007, Hepatology.

[26]  W. Muller,et al.  Different susceptibilities of PECAM-deficient mouse strains to spontaneous idiopathic pneumonitis. , 2006, Experimental and molecular pathology.

[27]  S. Nathan,et al.  Reversal of idiopathic pulmonary arterial hypertension and allograft pneumonectomy after single lung transplantation. , 2006, Chest.

[28]  David A. Schultz,et al.  A mechanosensory complex that mediates the endothelial cell response to fluid shear stress , 2005, Nature.

[29]  J. Frangos,et al.  PECAM-1 Mediates NO-Dependent Dilation of Arterioles to High Temporal Gradients of Shear Stress , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[30]  N. Voelkel,et al.  Initial apoptosis is followed by increased proliferation of apoptosis‐resistant endothelial cells , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[31]  J. Yuan,et al.  Pathogenesis of pulmonary arterial hypertension: the need for multiple hits. , 2005, Circulation.

[32]  R. Budhiraja,et al.  Endothelial Dysfunction in Pulmonary Hypertension , 2004, Circulation.

[33]  B. Engelhardt,et al.  Platelet endothelial cell adhesion molecule‐1 modulates endothelial cell motility through the small G‐protein Rho , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[34]  J. Stewart,et al.  A bradykinin antagonist and a caspase inhibitor prevent severe pulmonary hypertension in a rat model. , 2002, Canadian journal of physiology and pharmacology.

[35]  P. Hirth,et al.  Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death‐dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[36]  A. Mohsenin,et al.  PECAM‐1 shedding during apoptosis generates a membrane‐anchored truncated molecule with unique signaling characteristics , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[37]  R. L. Williams,et al.  Three-dimensional reconstruction of pulmonary arteries in plexiform pulmonary hypertension using cell-specific markers. Evidence for a dynamic and heterogeneous process of pulmonary endothelial cell growth. , 1999, The American journal of pathology.

[38]  M. Botney,et al.  Role of hemodynamics in pulmonary vascular remodeling: implications for primary pulmonary hypertension. , 1999, American journal of respiratory and critical care medicine.

[39]  Wei Zhang,et al.  Pulmonary hemodynamics modify the rat pulmonary artery response to injury. A neointimal model of pulmonary hypertension. , 1997, The American journal of pathology.

[40]  W. Williams,et al.  Pulmonary artery endothelial abnormalities in patients with congenital heart defects and pulmonary hypertension. A correlation of light with scanning electron microscopy and transmission electron microscopy. , 1986, Laboratory investigation; a journal of technical methods and pathology.

[41]  D. Heath,et al.  THE SMALL PULMONARY BLOOD VESSELS IN ATRIAL SEPTAL DEFECT , 1957, British heart journal.