Hypoxia and upregulation of hypoxia-inducible factor 1{alpha} stimulate venous thrombus recanalization
Angiogenic factors are expressed within thrombus during resolution, but the primary stimulus for neovascularization is unknown. Our aims were to determine whether (1) hypoxia and hypoxia-inducible factor 1α (HIF1α) are induced in resolving thrombus, (2) this stimulates angiogenic factor production,...
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| Veröffentlicht in: | Arteriosclerosis, thrombosis, and vascular biology thrombosis, and vascular biology, 2010-12, Vol.30 (12), p.2443-2451 |
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| creator | Evans, Colin Edward Humphries, Julia Mattock, Katherine Waltham, Matthew Wadoodi, Ashar Saha, Prakash Modarai, Bijan Maxwell, Patrick H Maxwell, Patrick J Smith, Alberto |
| description | Angiogenic factors are expressed within thrombus during resolution, but the primary stimulus for neovascularization is unknown. Our aims were to determine whether (1) hypoxia and hypoxia-inducible factor 1α (HIF1α) are induced in resolving thrombus, (2) this stimulates angiogenic factor production, and (3) upregulating HIF1α enhances thrombus resolution and vein recanalization.
Oxygen tension in the thrombus was negatively correlated with HIF1α levels (Spearman correlation [RS] = -0.77, P |
| doi_str_mv | 10.1161/ATVBAHA.110.215038 |
| format | Article |
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Oxygen tension in the thrombus was negatively correlated with HIF1α levels (Spearman correlation [RS] = -0.77, P<0.0001), whereas HIF1α levels positively correlated with vascular endothelial growth factor (VEGF) expression (Pearson correlation [R] = 0.85, P<0.0005), during resolution in a murine model. HIF1α (P<0.005), VEGF (P<0.005), and VEGF receptor 1 (VEGFR1) (P<0.05) expression was 2-fold greater in the thrombus of mice treated with the prolyl hydroxylase domain inhibitor L-mimosine compared with controls. The levels of 13 other HIF1-mediated angiogenic factors were also increased. Thrombus weight (P<0.001) and volume (P<0.05) were reduced by a third in l-mimosine-treated mice compared with controls, whereas vein recanalization (P<0.005) and thrombus neovascularization (P<0.001) were 2-fold greater, and this was associated with increased inflammatory cell content.
Hypoxia and HIF1α are induced in the naturally resolving thrombus and correlate with increased angiogenic factor expression. Upregulation of HIF1α enhances thrombus resolution and vein recanalization. HIF1α may represent a novel target for treatments that promote resolution and recanalization and reduce the incidence of post-thrombotic syndrome.]]></description><identifier>EISSN: 1524-4636</identifier><identifier>DOI: 10.1161/ATVBAHA.110.215038</identifier><identifier>PMID: 20930171</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Cell Hypoxia ; Cytokines - metabolism ; Disease Models, Animal ; Enzyme Inhibitors - pharmacology ; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism ; Macrophages - immunology ; Male ; Mice ; Mice, Inbred BALB C ; Mimosine - pharmacology ; Neovascularization, Physiologic - drug effects ; Neutrophil Infiltration ; Neutrophils - immunology ; Oxygen - metabolism ; Procollagen-Proline Dioxygenase - antagonists & inhibitors ; Procollagen-Proline Dioxygenase - metabolism ; Time Factors ; Up-Regulation ; Vascular Endothelial Growth Factor A - metabolism ; Vascular Endothelial Growth Factor Receptor-1 - metabolism ; Vena Cava, Inferior - drug effects ; Vena Cava, Inferior - immunology ; Vena Cava, Inferior - metabolism ; Venous Thrombosis - immunology ; Venous Thrombosis - metabolism ; Venous Thrombosis - physiopathology</subject><ispartof>Arteriosclerosis, thrombosis, and vascular biology, 2010-12, Vol.30 (12), p.2443-2451</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20930171$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Evans, Colin Edward</creatorcontrib><creatorcontrib>Humphries, Julia</creatorcontrib><creatorcontrib>Mattock, Katherine</creatorcontrib><creatorcontrib>Waltham, Matthew</creatorcontrib><creatorcontrib>Wadoodi, Ashar</creatorcontrib><creatorcontrib>Saha, Prakash</creatorcontrib><creatorcontrib>Modarai, Bijan</creatorcontrib><creatorcontrib>Maxwell, Patrick H</creatorcontrib><creatorcontrib>Maxwell, Patrick J</creatorcontrib><creatorcontrib>Smith, Alberto</creatorcontrib><title>Hypoxia and upregulation of hypoxia-inducible factor 1{alpha} stimulate venous thrombus recanalization</title><title>Arteriosclerosis, thrombosis, and vascular biology</title><addtitle>Arterioscler Thromb Vasc Biol</addtitle><description><![CDATA[Angiogenic factors are expressed within thrombus during resolution, but the primary stimulus for neovascularization is unknown. Our aims were to determine whether (1) hypoxia and hypoxia-inducible factor 1α (HIF1α) are induced in resolving thrombus, (2) this stimulates angiogenic factor production, and (3) upregulating HIF1α enhances thrombus resolution and vein recanalization.
Oxygen tension in the thrombus was negatively correlated with HIF1α levels (Spearman correlation [RS] = -0.77, P<0.0001), whereas HIF1α levels positively correlated with vascular endothelial growth factor (VEGF) expression (Pearson correlation [R] = 0.85, P<0.0005), during resolution in a murine model. HIF1α (P<0.005), VEGF (P<0.005), and VEGF receptor 1 (VEGFR1) (P<0.05) expression was 2-fold greater in the thrombus of mice treated with the prolyl hydroxylase domain inhibitor L-mimosine compared with controls. The levels of 13 other HIF1-mediated angiogenic factors were also increased. Thrombus weight (P<0.001) and volume (P<0.05) were reduced by a third in l-mimosine-treated mice compared with controls, whereas vein recanalization (P<0.005) and thrombus neovascularization (P<0.001) were 2-fold greater, and this was associated with increased inflammatory cell content.
Hypoxia and HIF1α are induced in the naturally resolving thrombus and correlate with increased angiogenic factor expression. Upregulation of HIF1α enhances thrombus resolution and vein recanalization. HIF1α may represent a novel target for treatments that promote resolution and recanalization and reduce the incidence of post-thrombotic syndrome.]]></description><subject>Animals</subject><subject>Cell Hypoxia</subject><subject>Cytokines - metabolism</subject><subject>Disease Models, Animal</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - metabolism</subject><subject>Macrophages - immunology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mimosine - pharmacology</subject><subject>Neovascularization, Physiologic - drug effects</subject><subject>Neutrophil Infiltration</subject><subject>Neutrophils - immunology</subject><subject>Oxygen - metabolism</subject><subject>Procollagen-Proline Dioxygenase - antagonists & inhibitors</subject><subject>Procollagen-Proline Dioxygenase - metabolism</subject><subject>Time Factors</subject><subject>Up-Regulation</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><subject>Vascular Endothelial Growth Factor Receptor-1 - metabolism</subject><subject>Vena Cava, Inferior - drug effects</subject><subject>Vena Cava, Inferior - immunology</subject><subject>Vena Cava, Inferior - metabolism</subject><subject>Venous Thrombosis - immunology</subject><subject>Venous Thrombosis - metabolism</subject><subject>Venous Thrombosis - physiopathology</subject><issn>1524-4636</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1UEFOwzAQtJAQLYUPcEC-cUqxYztJj6GiFKkSl4prtLHX1CiJg5MgCuLvBFpOszszO1oNIVeczTlP-G2-fb7L1_m4sHnMFRPZCZlyFctIJiKZkPOue2WMyThmZ2QSs4VgPOVTYtf71n84oNAYOrQBX4YKeucb6i3dHbTINWbQrqyQWtC9D5R_QdXu4Jt2vat_D5C-Y-OHjva74OtyHAJqaKByn39pF-TUQtXh5RFnZLu63y7X0ebp4XGZb6JWKR5ZphhgmqXcyAylTlKhtLFSKhAWJGoDpYUMsnShTKk4RzkSXKK1CmPQYkZuDrFt8G8Ddn1Ru05jVUGD43dFxjKpFolIR-f10TmUNZqiDa6GsC_-mxE_I_VoFg</recordid><startdate>201012</startdate><enddate>201012</enddate><creator>Evans, Colin Edward</creator><creator>Humphries, Julia</creator><creator>Mattock, Katherine</creator><creator>Waltham, Matthew</creator><creator>Wadoodi, Ashar</creator><creator>Saha, Prakash</creator><creator>Modarai, Bijan</creator><creator>Maxwell, Patrick H</creator><creator>Maxwell, Patrick J</creator><creator>Smith, Alberto</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>201012</creationdate><title>Hypoxia and upregulation of hypoxia-inducible factor 1{alpha} stimulate venous thrombus recanalization</title><author>Evans, Colin Edward ; Humphries, Julia ; Mattock, Katherine ; Waltham, Matthew ; Wadoodi, Ashar ; Saha, Prakash ; Modarai, Bijan ; Maxwell, Patrick H ; Maxwell, Patrick J ; Smith, Alberto</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p551-f050ae7871d48e4c6735cdf445a3fa4ecdabfa8a8795db511e4abf14eff5e2ac3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Cell Hypoxia</topic><topic>Cytokines - metabolism</topic><topic>Disease Models, Animal</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - metabolism</topic><topic>Macrophages - immunology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mimosine - pharmacology</topic><topic>Neovascularization, Physiologic - drug effects</topic><topic>Neutrophil Infiltration</topic><topic>Neutrophils - immunology</topic><topic>Oxygen - metabolism</topic><topic>Procollagen-Proline Dioxygenase - antagonists & inhibitors</topic><topic>Procollagen-Proline Dioxygenase - metabolism</topic><topic>Time Factors</topic><topic>Up-Regulation</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><topic>Vascular Endothelial Growth Factor Receptor-1 - metabolism</topic><topic>Vena Cava, Inferior - drug effects</topic><topic>Vena Cava, Inferior - immunology</topic><topic>Vena Cava, Inferior - metabolism</topic><topic>Venous Thrombosis - immunology</topic><topic>Venous Thrombosis - metabolism</topic><topic>Venous Thrombosis - physiopathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Evans, Colin Edward</creatorcontrib><creatorcontrib>Humphries, Julia</creatorcontrib><creatorcontrib>Mattock, Katherine</creatorcontrib><creatorcontrib>Waltham, Matthew</creatorcontrib><creatorcontrib>Wadoodi, Ashar</creatorcontrib><creatorcontrib>Saha, Prakash</creatorcontrib><creatorcontrib>Modarai, Bijan</creatorcontrib><creatorcontrib>Maxwell, Patrick H</creatorcontrib><creatorcontrib>Maxwell, Patrick J</creatorcontrib><creatorcontrib>Smith, Alberto</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Arteriosclerosis, thrombosis, and vascular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Evans, Colin Edward</au><au>Humphries, Julia</au><au>Mattock, Katherine</au><au>Waltham, Matthew</au><au>Wadoodi, Ashar</au><au>Saha, Prakash</au><au>Modarai, Bijan</au><au>Maxwell, Patrick H</au><au>Maxwell, Patrick J</au><au>Smith, Alberto</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hypoxia and upregulation of hypoxia-inducible factor 1{alpha} stimulate venous thrombus recanalization</atitle><jtitle>Arteriosclerosis, thrombosis, and vascular biology</jtitle><addtitle>Arterioscler Thromb Vasc Biol</addtitle><date>2010-12</date><risdate>2010</risdate><volume>30</volume><issue>12</issue><spage>2443</spage><epage>2451</epage><pages>2443-2451</pages><eissn>1524-4636</eissn><abstract><![CDATA[Angiogenic factors are expressed within thrombus during resolution, but the primary stimulus for neovascularization is unknown. Our aims were to determine whether (1) hypoxia and hypoxia-inducible factor 1α (HIF1α) are induced in resolving thrombus, (2) this stimulates angiogenic factor production, and (3) upregulating HIF1α enhances thrombus resolution and vein recanalization.
Oxygen tension in the thrombus was negatively correlated with HIF1α levels (Spearman correlation [RS] = -0.77, P<0.0001), whereas HIF1α levels positively correlated with vascular endothelial growth factor (VEGF) expression (Pearson correlation [R] = 0.85, P<0.0005), during resolution in a murine model. HIF1α (P<0.005), VEGF (P<0.005), and VEGF receptor 1 (VEGFR1) (P<0.05) expression was 2-fold greater in the thrombus of mice treated with the prolyl hydroxylase domain inhibitor L-mimosine compared with controls. The levels of 13 other HIF1-mediated angiogenic factors were also increased. Thrombus weight (P<0.001) and volume (P<0.05) were reduced by a third in l-mimosine-treated mice compared with controls, whereas vein recanalization (P<0.005) and thrombus neovascularization (P<0.001) were 2-fold greater, and this was associated with increased inflammatory cell content.
Hypoxia and HIF1α are induced in the naturally resolving thrombus and correlate with increased angiogenic factor expression. Upregulation of HIF1α enhances thrombus resolution and vein recanalization. HIF1α may represent a novel target for treatments that promote resolution and recanalization and reduce the incidence of post-thrombotic syndrome.]]></abstract><cop>United States</cop><pmid>20930171</pmid><doi>10.1161/ATVBAHA.110.215038</doi><tpages>9</tpages></addata></record> |
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| subjects | Animals Cell Hypoxia Cytokines - metabolism Disease Models, Animal Enzyme Inhibitors - pharmacology Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Macrophages - immunology Male Mice Mice, Inbred BALB C Mimosine - pharmacology Neovascularization, Physiologic - drug effects Neutrophil Infiltration Neutrophils - immunology Oxygen - metabolism Procollagen-Proline Dioxygenase - antagonists & inhibitors Procollagen-Proline Dioxygenase - metabolism Time Factors Up-Regulation Vascular Endothelial Growth Factor A - metabolism Vascular Endothelial Growth Factor Receptor-1 - metabolism Vena Cava, Inferior - drug effects Vena Cava, Inferior - immunology Vena Cava, Inferior - metabolism Venous Thrombosis - immunology Venous Thrombosis - metabolism Venous Thrombosis - physiopathology |
| title | Hypoxia and upregulation of hypoxia-inducible factor 1{alpha} stimulate venous thrombus recanalization |
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