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RNA-Sequencing Highlights Inflammation and Impaired Integrity of the Vascular Wall in Brain Arteriovenous Malformations
BACKGROUND AND PURPOSE—Interventional treatment of unruptured brain arteriovenous malformations (BAVMs) has become increasingly controversial. Because medical therapy is still lacking, we aimed to obtain insight into the disease mechanisms implicated in BAVMs and to identify potential targets for me...
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| Published in: | Stroke (1970) 2020-01, Vol.51 (1), p.268-274 |
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| container_end_page | 274 |
| container_issue | 1 |
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| container_title | Stroke (1970) |
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| creator | Hauer, Allard J Kleinloog, Rachel Giuliani, Fabrizio Rinkel, Gabriël J.E de Kort, Gerard A Berkelbach van der Sprenkel, Jan Willem van der Zwan, Albert Gosselaar, Peter H van Rijen, Peter C de Boer-Bergsma, Jelkje J Deelen, Patrick Swertz, Morris A De Muynck, Louis Van Damme, Philip Veldink, Jan H Ruigrok, Ynte M Klijn, Catharina J.M |
| description | BACKGROUND AND PURPOSE—Interventional treatment of unruptured brain arteriovenous malformations (BAVMs) has become increasingly controversial. Because medical therapy is still lacking, we aimed to obtain insight into the disease mechanisms implicated in BAVMs and to identify potential targets for medical treatment to prevent rupture of a BAVM.
METHODS—We used next-generation RNA sequencing to identify differential expression on a transcriptome-wide level comparing tissue samples of 12 BAVMs to 16 intracranial control arteries. We identified differentially expressed genes by negative binominal generalized log-linear regression (false discovery rate corrected P |
| doi_str_mv | 10.1161/STROKEAHA.119.025657 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2321661624</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2321661624</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4537-5833cd0a6d6f5c491075727c36d704401dd2b1fba1af5c85b6b84f9f65ec9bdc3</originalsourceid><addsrcrecordid>eNp9kE1P3DAQhq2qCJaPf1BVPvYS8HfiY0C0u-JLAtoeI8exd10cZ2snXfHvcRXgyGFmPPI7r8cPAF8wOsVY4LOHx_u7q8t6WedWniLCBS8_gQXmhBVMkOozWCBEZUGYlAfgMKU_CCFCK74PDiguJZeILMDu_rYuHszfyQTtwhou3Xrjc4wJroL1qu_V6IYAVejgqt8qF00-hNGsoxuf4WDhuDHwl0p68irC38p76AI8jyrnOo4muuGfCcOU4I3ydoizXzoGe1b5ZE5e6xH4-f3y8WJZXN_9WF3U14VmnJYFryjVHVKiE5ZrJjEqeUlKTUVXIsYQ7jrSYtsqrPJ9xVvRVsxKK7jRsu00PQLfZt9tHPIn09j0LmnjvQomL9UQSrAQWBCWpWyW6jikFI1tttH1Kj43GDX_kTfvyHMrmxl5Hvv6-sLU9qZ7H3pjnAXVLNgNPvNIT37amdhsjPLj5mPvFwZ_kRg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2321661624</pqid></control><display><type>article</type><title>RNA-Sequencing Highlights Inflammation and Impaired Integrity of the Vascular Wall in Brain Arteriovenous Malformations</title><source>Alma/SFX Local Collection</source><creator>Hauer, Allard J ; Kleinloog, Rachel ; Giuliani, Fabrizio ; Rinkel, Gabriël J.E ; de Kort, Gerard A ; Berkelbach van der Sprenkel, Jan Willem ; van der Zwan, Albert ; Gosselaar, Peter H ; van Rijen, Peter C ; de Boer-Bergsma, Jelkje J ; Deelen, Patrick ; Swertz, Morris A ; De Muynck, Louis ; Van Damme, Philip ; Veldink, Jan H ; Ruigrok, Ynte M ; Klijn, Catharina J.M</creator><creatorcontrib>Hauer, Allard J ; Kleinloog, Rachel ; Giuliani, Fabrizio ; Rinkel, Gabriël J.E ; de Kort, Gerard A ; Berkelbach van der Sprenkel, Jan Willem ; van der Zwan, Albert ; Gosselaar, Peter H ; van Rijen, Peter C ; de Boer-Bergsma, Jelkje J ; Deelen, Patrick ; Swertz, Morris A ; De Muynck, Louis ; Van Damme, Philip ; Veldink, Jan H ; Ruigrok, Ynte M ; Klijn, Catharina J.M</creatorcontrib><description>BACKGROUND AND PURPOSE—Interventional treatment of unruptured brain arteriovenous malformations (BAVMs) has become increasingly controversial. Because medical therapy is still lacking, we aimed to obtain insight into the disease mechanisms implicated in BAVMs and to identify potential targets for medical treatment to prevent rupture of a BAVM.
METHODS—We used next-generation RNA sequencing to identify differential expression on a transcriptome-wide level comparing tissue samples of 12 BAVMs to 16 intracranial control arteries. We identified differentially expressed genes by negative binominal generalized log-linear regression (false discovery rate corrected P<0.05). We selected 10 genes for validation using droplet digital polymerase chain reaction. We performed functional pathway analysis accounting for potential gene-length bias, to establish enhancement of biological pathways involved in BAVMs. We further assessed which Gene Ontology terms were enriched.
RESULTS—We found 736 upregulated genes in BAVMs including genes implicated in the cytoskeletal machinery and cell-migration and genes encoding for inflammatory cytokines and secretory products of neutrophils and macrophages. Furthermore, we found 498 genes downregulated including genes implicated in extracellular matrix composition, the binary angiopoietin-TIE system, and TGF (transforming growth factor)-β signaling. We confirmed the differential expression of top 10 ranked genes. Functional pathway analysis showed enrichment of the protein digestion and absorption pathway (false discovery rate-adjusted P=1.70×10). We identified 47 enriched Gene Ontology terms (false discovery rate-adjusted P<0.05) implicated in cytoskeleton network, cell-migration, endoplasmic reticulum, transmembrane transport, and extracellular matrix composition.
CONCLUSIONS—Our genome-wide RNA-sequencing study points to involvement of inflammatory mediators, loss of cerebrovascular quiescence, and impaired integrity of the vascular wall in the pathophysiology of BAVMs. Our study may lend support to potential receptivity of BAVMs to medical therapeutics, including those promoting vessel maturation, and anti-inflammatory and immune-modifying drugs.</description><identifier>ISSN: 0039-2499</identifier><identifier>EISSN: 1524-4628</identifier><identifier>DOI: 10.1161/STROKEAHA.119.025657</identifier><identifier>PMID: 31795902</identifier><language>eng</language><publisher>United States: American Heart Association, Inc</publisher><subject>Adult ; Aged ; Brain - metabolism ; Female ; Gene Expression Regulation ; High-Throughput Nucleotide Sequencing ; Humans ; Inflammation - genetics ; Inflammation - metabolism ; Inflammation - pathology ; Intracranial Arteriovenous Malformations - genetics ; Intracranial Arteriovenous Malformations - metabolism ; Intracranial Arteriovenous Malformations - pathology ; Male ; Middle Aged ; Retrospective Studies ; Sequence Analysis, RNA</subject><ispartof>Stroke (1970), 2020-01, Vol.51 (1), p.268-274</ispartof><rights>2020 American Heart Association, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4537-5833cd0a6d6f5c491075727c36d704401dd2b1fba1af5c85b6b84f9f65ec9bdc3</citedby><cites>FETCH-LOGICAL-c4537-5833cd0a6d6f5c491075727c36d704401dd2b1fba1af5c85b6b84f9f65ec9bdc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31795902$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hauer, Allard J</creatorcontrib><creatorcontrib>Kleinloog, Rachel</creatorcontrib><creatorcontrib>Giuliani, Fabrizio</creatorcontrib><creatorcontrib>Rinkel, Gabriël J.E</creatorcontrib><creatorcontrib>de Kort, Gerard A</creatorcontrib><creatorcontrib>Berkelbach van der Sprenkel, Jan Willem</creatorcontrib><creatorcontrib>van der Zwan, Albert</creatorcontrib><creatorcontrib>Gosselaar, Peter H</creatorcontrib><creatorcontrib>van Rijen, Peter C</creatorcontrib><creatorcontrib>de Boer-Bergsma, Jelkje J</creatorcontrib><creatorcontrib>Deelen, Patrick</creatorcontrib><creatorcontrib>Swertz, Morris A</creatorcontrib><creatorcontrib>De Muynck, Louis</creatorcontrib><creatorcontrib>Van Damme, Philip</creatorcontrib><creatorcontrib>Veldink, Jan H</creatorcontrib><creatorcontrib>Ruigrok, Ynte M</creatorcontrib><creatorcontrib>Klijn, Catharina J.M</creatorcontrib><title>RNA-Sequencing Highlights Inflammation and Impaired Integrity of the Vascular Wall in Brain Arteriovenous Malformations</title><title>Stroke (1970)</title><addtitle>Stroke</addtitle><description>BACKGROUND AND PURPOSE—Interventional treatment of unruptured brain arteriovenous malformations (BAVMs) has become increasingly controversial. Because medical therapy is still lacking, we aimed to obtain insight into the disease mechanisms implicated in BAVMs and to identify potential targets for medical treatment to prevent rupture of a BAVM.
METHODS—We used next-generation RNA sequencing to identify differential expression on a transcriptome-wide level comparing tissue samples of 12 BAVMs to 16 intracranial control arteries. We identified differentially expressed genes by negative binominal generalized log-linear regression (false discovery rate corrected P<0.05). We selected 10 genes for validation using droplet digital polymerase chain reaction. We performed functional pathway analysis accounting for potential gene-length bias, to establish enhancement of biological pathways involved in BAVMs. We further assessed which Gene Ontology terms were enriched.
RESULTS—We found 736 upregulated genes in BAVMs including genes implicated in the cytoskeletal machinery and cell-migration and genes encoding for inflammatory cytokines and secretory products of neutrophils and macrophages. Furthermore, we found 498 genes downregulated including genes implicated in extracellular matrix composition, the binary angiopoietin-TIE system, and TGF (transforming growth factor)-β signaling. We confirmed the differential expression of top 10 ranked genes. Functional pathway analysis showed enrichment of the protein digestion and absorption pathway (false discovery rate-adjusted P=1.70×10). We identified 47 enriched Gene Ontology terms (false discovery rate-adjusted P<0.05) implicated in cytoskeleton network, cell-migration, endoplasmic reticulum, transmembrane transport, and extracellular matrix composition.
CONCLUSIONS—Our genome-wide RNA-sequencing study points to involvement of inflammatory mediators, loss of cerebrovascular quiescence, and impaired integrity of the vascular wall in the pathophysiology of BAVMs. Our study may lend support to potential receptivity of BAVMs to medical therapeutics, including those promoting vessel maturation, and anti-inflammatory and immune-modifying drugs.</description><subject>Adult</subject><subject>Aged</subject><subject>Brain - metabolism</subject><subject>Female</subject><subject>Gene Expression Regulation</subject><subject>High-Throughput Nucleotide Sequencing</subject><subject>Humans</subject><subject>Inflammation - genetics</subject><subject>Inflammation - metabolism</subject><subject>Inflammation - pathology</subject><subject>Intracranial Arteriovenous Malformations - genetics</subject><subject>Intracranial Arteriovenous Malformations - metabolism</subject><subject>Intracranial Arteriovenous Malformations - pathology</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Retrospective Studies</subject><subject>Sequence Analysis, RNA</subject><issn>0039-2499</issn><issn>1524-4628</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kE1P3DAQhq2qCJaPf1BVPvYS8HfiY0C0u-JLAtoeI8exd10cZ2snXfHvcRXgyGFmPPI7r8cPAF8wOsVY4LOHx_u7q8t6WedWniLCBS8_gQXmhBVMkOozWCBEZUGYlAfgMKU_CCFCK74PDiguJZeILMDu_rYuHszfyQTtwhou3Xrjc4wJroL1qu_V6IYAVejgqt8qF00-hNGsoxuf4WDhuDHwl0p68irC38p76AI8jyrnOo4muuGfCcOU4I3ydoizXzoGe1b5ZE5e6xH4-f3y8WJZXN_9WF3U14VmnJYFryjVHVKiE5ZrJjEqeUlKTUVXIsYQ7jrSYtsqrPJ9xVvRVsxKK7jRsu00PQLfZt9tHPIn09j0LmnjvQomL9UQSrAQWBCWpWyW6jikFI1tttH1Kj43GDX_kTfvyHMrmxl5Hvv6-sLU9qZ7H3pjnAXVLNgNPvNIT37amdhsjPLj5mPvFwZ_kRg</recordid><startdate>202001</startdate><enddate>202001</enddate><creator>Hauer, Allard J</creator><creator>Kleinloog, Rachel</creator><creator>Giuliani, Fabrizio</creator><creator>Rinkel, Gabriël J.E</creator><creator>de Kort, Gerard A</creator><creator>Berkelbach van der Sprenkel, Jan Willem</creator><creator>van der Zwan, Albert</creator><creator>Gosselaar, Peter H</creator><creator>van Rijen, Peter C</creator><creator>de Boer-Bergsma, Jelkje J</creator><creator>Deelen, Patrick</creator><creator>Swertz, Morris A</creator><creator>De Muynck, Louis</creator><creator>Van Damme, Philip</creator><creator>Veldink, Jan H</creator><creator>Ruigrok, Ynte M</creator><creator>Klijn, Catharina J.M</creator><general>American Heart Association, Inc</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>7X8</scope></search><sort><creationdate>202001</creationdate><title>RNA-Sequencing Highlights Inflammation and Impaired Integrity of the Vascular Wall in Brain Arteriovenous Malformations</title><author>Hauer, Allard J ; 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Because medical therapy is still lacking, we aimed to obtain insight into the disease mechanisms implicated in BAVMs and to identify potential targets for medical treatment to prevent rupture of a BAVM.
METHODS—We used next-generation RNA sequencing to identify differential expression on a transcriptome-wide level comparing tissue samples of 12 BAVMs to 16 intracranial control arteries. We identified differentially expressed genes by negative binominal generalized log-linear regression (false discovery rate corrected P<0.05). We selected 10 genes for validation using droplet digital polymerase chain reaction. We performed functional pathway analysis accounting for potential gene-length bias, to establish enhancement of biological pathways involved in BAVMs. We further assessed which Gene Ontology terms were enriched.
RESULTS—We found 736 upregulated genes in BAVMs including genes implicated in the cytoskeletal machinery and cell-migration and genes encoding for inflammatory cytokines and secretory products of neutrophils and macrophages. Furthermore, we found 498 genes downregulated including genes implicated in extracellular matrix composition, the binary angiopoietin-TIE system, and TGF (transforming growth factor)-β signaling. We confirmed the differential expression of top 10 ranked genes. Functional pathway analysis showed enrichment of the protein digestion and absorption pathway (false discovery rate-adjusted P=1.70×10). We identified 47 enriched Gene Ontology terms (false discovery rate-adjusted P<0.05) implicated in cytoskeleton network, cell-migration, endoplasmic reticulum, transmembrane transport, and extracellular matrix composition.
CONCLUSIONS—Our genome-wide RNA-sequencing study points to involvement of inflammatory mediators, loss of cerebrovascular quiescence, and impaired integrity of the vascular wall in the pathophysiology of BAVMs. Our study may lend support to potential receptivity of BAVMs to medical therapeutics, including those promoting vessel maturation, and anti-inflammatory and immune-modifying drugs.</abstract><cop>United States</cop><pub>American Heart Association, Inc</pub><pmid>31795902</pmid><doi>10.1161/STROKEAHA.119.025657</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Stroke (1970), 2020-01, Vol.51 (1), p.268-274 |
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| subjects | Adult Aged Brain - metabolism Female Gene Expression Regulation High-Throughput Nucleotide Sequencing Humans Inflammation - genetics Inflammation - metabolism Inflammation - pathology Intracranial Arteriovenous Malformations - genetics Intracranial Arteriovenous Malformations - metabolism Intracranial Arteriovenous Malformations - pathology Male Middle Aged Retrospective Studies Sequence Analysis, RNA |
| title | RNA-Sequencing Highlights Inflammation and Impaired Integrity of the Vascular Wall in Brain Arteriovenous Malformations |
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