Delayed Microvascular Shear Adaptation in Pulmonary Arterial Hypertension. Role of Platelet Endothelial Cell Adhesion Molecule-1 Cleavage
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. We hypothesize that failing shear adaptati...
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| Veröffentlicht in: | American journal of respiratory and critical care medicine 2016-06, Vol.193 (12), p.1410-1420 |
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| creator | Szulcek, Robert Happé, Chris M Rol, Nina Fontijn, Ruud D Dickhoff, Chris Hartemink, Koen J Grünberg, Katrien Tu, Ly Timens, Wim Nossent, George D Paul, Marinus A Leyen, Thomas A Horrevoets, Anton J de Man, Frances S Guignabert, Christophe Yu, Paul B Vonk-Noordegraaf, Anton van Nieuw Amerongen, Geerten P Bogaard, Harm J |
| description | 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.
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.
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.
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.
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. |
| doi_str_mv | 10.1164/rccm.201506-1231OC |
| format | Article |
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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.
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.
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.
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.</description><identifier>ISSN: 1073-449X</identifier><identifier>EISSN: 1535-4970</identifier><identifier>DOI: 10.1164/rccm.201506-1231OC</identifier><identifier>PMID: 26760925</identifier><language>eng</language><publisher>United States: American Thoracic Society</publisher><subject>Adult ; Animals ; Blotting, Western ; Cells, Cultured ; Child ; Disease Models, Animal ; Female ; Fluorescent Antibody Technique ; Humans ; Hypertension, Pulmonary - metabolism ; Hypertension, Pulmonary - physiopathology ; Male ; Microvessels - metabolism ; Microvessels - physiopathology ; Middle Aged ; Original ; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism ; Polymerase Chain Reaction ; Pulmonary Artery - metabolism ; Pulmonary Artery - physiopathology ; Rats ; Vascular Remodeling - physiology ; Young Adult</subject><ispartof>American journal of respiratory and critical care medicine, 2016-06, Vol.193 (12), p.1410-1420</ispartof><rights>Copyright American Thoracic Society Jun 15, 2016</rights><rights>Copyright © 2016 by the American Thoracic Society 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c430t-4d6e4d90fb2e87b8be823a81026f3b385dc1472d4134194cec5c1f1374b4be513</citedby><cites>FETCH-LOGICAL-c430t-4d6e4d90fb2e87b8be823a81026f3b385dc1472d4134194cec5c1f1374b4be513</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,778,782,883,4013,27911,27912</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26760925$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Szulcek, Robert</creatorcontrib><creatorcontrib>Happé, Chris M</creatorcontrib><creatorcontrib>Rol, Nina</creatorcontrib><creatorcontrib>Fontijn, Ruud D</creatorcontrib><creatorcontrib>Dickhoff, Chris</creatorcontrib><creatorcontrib>Hartemink, Koen J</creatorcontrib><creatorcontrib>Grünberg, Katrien</creatorcontrib><creatorcontrib>Tu, Ly</creatorcontrib><creatorcontrib>Timens, Wim</creatorcontrib><creatorcontrib>Nossent, George D</creatorcontrib><creatorcontrib>Paul, Marinus A</creatorcontrib><creatorcontrib>Leyen, Thomas A</creatorcontrib><creatorcontrib>Horrevoets, Anton J</creatorcontrib><creatorcontrib>de Man, Frances S</creatorcontrib><creatorcontrib>Guignabert, Christophe</creatorcontrib><creatorcontrib>Yu, Paul B</creatorcontrib><creatorcontrib>Vonk-Noordegraaf, Anton</creatorcontrib><creatorcontrib>van Nieuw Amerongen, Geerten P</creatorcontrib><creatorcontrib>Bogaard, Harm J</creatorcontrib><title>Delayed Microvascular Shear Adaptation in Pulmonary Arterial Hypertension. Role of Platelet Endothelial Cell Adhesion Molecule-1 Cleavage</title><title>American journal of respiratory and critical care medicine</title><addtitle>Am J Respir Crit Care Med</addtitle><description>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.
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.
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.
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.
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.</description><subject>Adult</subject><subject>Animals</subject><subject>Blotting, Western</subject><subject>Cells, Cultured</subject><subject>Child</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Fluorescent Antibody Technique</subject><subject>Humans</subject><subject>Hypertension, Pulmonary - metabolism</subject><subject>Hypertension, Pulmonary - physiopathology</subject><subject>Male</subject><subject>Microvessels - metabolism</subject><subject>Microvessels - physiopathology</subject><subject>Middle Aged</subject><subject>Original</subject><subject>Platelet Endothelial Cell Adhesion Molecule-1 - metabolism</subject><subject>Polymerase Chain Reaction</subject><subject>Pulmonary Artery - metabolism</subject><subject>Pulmonary Artery - physiopathology</subject><subject>Rats</subject><subject>Vascular Remodeling - physiology</subject><subject>Young Adult</subject><issn>1073-449X</issn><issn>1535-4970</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNpdkc1u1TAQhSMEoqXwAiyQJTZscvH4L8kG6SoUitSqFT8SO8txJr2pnPjWTq50H4G3xlFKBWxmRvI3Z3x0suw10A2AEu-DtcOGUZBU5cA4XNdPslOQXOaiKujTNNOC50JUP0-yFzHeUQqsBPo8O2GqULRi8jT79RGdOWJLrnob_MFEOzsTyLcdprptzX4yU-9H0o_kZnaDH004km2YMPTGkYvjHtM8xoRsyFfvkPiO3DgzocOJnI-tn3boFrRG55LgDheWXCU0XcIcSO3QHMwtvsyedcZFfPXQz7Ifn86_1xf55fXnL_X2MreC0ykXrULRVrRrGJZFUzZYMm6SLaY63vBSthZEwVoBXEAlLFppoQNeiEY0KIGfZR9W3f3cDNhaHKdgnN6HfkjetDe9_vdl7Hf61h-0qkCWkieBdw8Cwd_PGCc99NEme2ZEP0cNRVWUSolqufX2P_TOz2FM9laqlIIuFFuplECMAbvHzwDVS9J6SVqvSes16bT05m8bjyt_ouW_AdNFp4Y</recordid><startdate>20160615</startdate><enddate>20160615</enddate><creator>Szulcek, Robert</creator><creator>Happé, Chris M</creator><creator>Rol, Nina</creator><creator>Fontijn, Ruud D</creator><creator>Dickhoff, Chris</creator><creator>Hartemink, Koen J</creator><creator>Grünberg, Katrien</creator><creator>Tu, Ly</creator><creator>Timens, Wim</creator><creator>Nossent, George D</creator><creator>Paul, Marinus A</creator><creator>Leyen, Thomas A</creator><creator>Horrevoets, Anton J</creator><creator>de Man, Frances S</creator><creator>Guignabert, Christophe</creator><creator>Yu, Paul B</creator><creator>Vonk-Noordegraaf, Anton</creator><creator>van Nieuw Amerongen, Geerten P</creator><creator>Bogaard, Harm J</creator><general>American Thoracic Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20160615</creationdate><title>Delayed Microvascular Shear Adaptation in Pulmonary Arterial Hypertension. 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American journal of respiratory and critical care medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Szulcek, Robert</au><au>Happé, Chris M</au><au>Rol, Nina</au><au>Fontijn, Ruud D</au><au>Dickhoff, Chris</au><au>Hartemink, Koen J</au><au>Grünberg, Katrien</au><au>Tu, Ly</au><au>Timens, Wim</au><au>Nossent, George D</au><au>Paul, Marinus A</au><au>Leyen, Thomas A</au><au>Horrevoets, Anton J</au><au>de Man, Frances S</au><au>Guignabert, Christophe</au><au>Yu, Paul B</au><au>Vonk-Noordegraaf, Anton</au><au>van Nieuw Amerongen, Geerten P</au><au>Bogaard, Harm J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Delayed Microvascular Shear Adaptation in Pulmonary Arterial Hypertension. Role of Platelet Endothelial Cell Adhesion Molecule-1 Cleavage</atitle><jtitle>American journal of respiratory and critical care medicine</jtitle><addtitle>Am J Respir Crit Care Med</addtitle><date>2016-06-15</date><risdate>2016</risdate><volume>193</volume><issue>12</issue><spage>1410</spage><epage>1420</epage><pages>1410-1420</pages><issn>1073-449X</issn><eissn>1535-4970</eissn><abstract>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.
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.
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.
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.
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.</abstract><cop>United States</cop><pub>American Thoracic Society</pub><pmid>26760925</pmid><doi>10.1164/rccm.201506-1231OC</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Animals Blotting, Western Cells, Cultured Child Disease Models, Animal Female Fluorescent Antibody Technique Humans Hypertension, Pulmonary - metabolism Hypertension, Pulmonary - physiopathology Male Microvessels - metabolism Microvessels - physiopathology Middle Aged Original Platelet Endothelial Cell Adhesion Molecule-1 - metabolism Polymerase Chain Reaction Pulmonary Artery - metabolism Pulmonary Artery - physiopathology Rats Vascular Remodeling - physiology Young Adult |
| title | Delayed Microvascular Shear Adaptation in Pulmonary Arterial Hypertension. Role of Platelet Endothelial Cell Adhesion Molecule-1 Cleavage |
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