Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies
Thoracic aortic aneurysms (TAA) are permanent and localized dilations of the aorta that predispose patients to a life-threatening risk of aortic dissection or rupture. The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required...
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description | Thoracic aortic aneurysms (TAA) are permanent and localized dilations of the aorta that predispose patients to a life-threatening risk of aortic dissection or rupture. The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required to maintain aortic homeostasis. Vascular smooth muscle cells (VSMCs) elaborate and remodel the extracellular matrix (ECM) in response to mechanical and biochemical cues from their environment. Causal variants for hereditary forms of aneurysm compromise the function of gene products involved in the transmission or interpretation of these signals, initiating processes that eventually lead to degeneration and mechanical failure of the vessel. These include mutations that interfere with transduction of stimuli from the matrix to the actin-myosin cytoskeleton through integrins, and those that impair signaling pathways activated by transforming growth factor-β (TGF-β). In this review, we summarize the features of the healthy aortic wall, the major pathways involved in the modulation of VSMC phenotypes, and the basic molecular functions impaired by TAA-associated mutations. We also discuss how the heterogeneity and balance of adaptive and maladaptive responses to the initial genetic insult might contribute to disease. |
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The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required to maintain aortic homeostasis. Vascular smooth muscle cells (VSMCs) elaborate and remodel the extracellular matrix (ECM) in response to mechanical and biochemical cues from their environment. Causal variants for hereditary forms of aneurysm compromise the function of gene products involved in the transmission or interpretation of these signals, initiating processes that eventually lead to degeneration and mechanical failure of the vessel. These include mutations that interfere with transduction of stimuli from the matrix to the actin-myosin cytoskeleton through integrins, and those that impair signaling pathways activated by transforming growth factor-β (TGF-β). In this review, we summarize the features of the healthy aortic wall, the major pathways involved in the modulation of VSMC phenotypes, and the basic molecular functions impaired by TAA-associated mutations. We also discuss how the heterogeneity and balance of adaptive and maladaptive responses to the initial genetic insult might contribute to disease.</description><identifier>ISSN: 2073-4425</identifier><identifier>EISSN: 2073-4425</identifier><identifier>DOI: 10.3390/genes12020183</identifier><identifier>PMID: 33514025</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Actin ; Adaptation, Physiological ; Alleles ; Aneurysms ; Animals ; Aorta ; Aortic Aneurysm, Thoracic - diagnosis ; Aortic Aneurysm, Thoracic - genetics ; Aortic Aneurysm, Thoracic - metabolism ; Aortic Aneurysm, Thoracic - therapy ; Aortic aneurysms ; Biomarkers ; Clinical Decision-Making ; Collagen ; Coronary vessels ; Cytoskeleton ; Degeneration ; Disease Management ; Dissection ; Extracellular matrix ; Extracellular Matrix - genetics ; Fibroblasts ; Genetic Association Studies - methods ; Genetic Predisposition to Disease ; Genotype ; Genotype & phenotype ; Growth factors ; Homeostasis ; Humans ; Integrins ; Ligands ; Muscle, Smooth, Vascular - metabolism ; Mutation ; Myocytes, Smooth Muscle - metabolism ; Myosin ; Pathogenesis ; Phenotype ; Phenotypes ; Physiology ; Proteins ; Review ; Signal Transduction ; Smooth muscle ; Thorax ; Transforming growth factor-b ; Veins & arteries</subject><ispartof>Genes, 2021-01, Vol.12 (2), p.183</ispartof><rights>2021. This work is licensed under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). 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In this review, we summarize the features of the healthy aortic wall, the major pathways involved in the modulation of VSMC phenotypes, and the basic molecular functions impaired by TAA-associated mutations. We also discuss how the heterogeneity and balance of adaptive and maladaptive responses to the initial genetic insult might contribute to disease.</description><subject>Actin</subject><subject>Adaptation, Physiological</subject><subject>Alleles</subject><subject>Aneurysms</subject><subject>Animals</subject><subject>Aorta</subject><subject>Aortic Aneurysm, Thoracic - diagnosis</subject><subject>Aortic Aneurysm, Thoracic - genetics</subject><subject>Aortic Aneurysm, Thoracic - metabolism</subject><subject>Aortic Aneurysm, Thoracic - therapy</subject><subject>Aortic aneurysms</subject><subject>Biomarkers</subject><subject>Clinical Decision-Making</subject><subject>Collagen</subject><subject>Coronary vessels</subject><subject>Cytoskeleton</subject><subject>Degeneration</subject><subject>Disease Management</subject><subject>Dissection</subject><subject>Extracellular matrix</subject><subject>Extracellular Matrix - genetics</subject><subject>Fibroblasts</subject><subject>Genetic Association Studies - methods</subject><subject>Genetic Predisposition to Disease</subject><subject>Genotype</subject><subject>Genotype & phenotype</subject><subject>Growth factors</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Integrins</subject><subject>Ligands</subject><subject>Muscle, Smooth, Vascular - metabolism</subject><subject>Mutation</subject><subject>Myocytes, Smooth Muscle - metabolism</subject><subject>Myosin</subject><subject>Pathogenesis</subject><subject>Phenotype</subject><subject>Phenotypes</subject><subject>Physiology</subject><subject>Proteins</subject><subject>Review</subject><subject>Signal Transduction</subject><subject>Smooth muscle</subject><subject>Thorax</subject><subject>Transforming growth factor-b</subject><subject>Veins & arteries</subject><issn>2073-4425</issn><issn>2073-4425</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kc1LwzAYxoMobswdvUrBi5dq0iRrexHGUDcYKOjOIU3frh1tM5NU2H9v9uFwHswhX-_vfXheHoSuCb6nNMUPS2jBkghHmCT0DPUjHNOQsYif_7r30NDaFfaLeRDzS9SjlBP_4H20mLW2WpbOBroNXAnBm3Sl3ulW_q8Ixi10ZmMbXzS6W5Y76N11-WZbnYKBvHLSbIKxNk6vfXcF9gpdFLK2MDycA7R4fvqYTMP568tsMp6HiuPUhYol3k-e0Yz5DQPNYsBFLHlKCsK9_0yygqcMZKGA51ilRaxkmlMuKY6logP0uNddd1kDuYLWGVmLtakab0loWYnTSluVYqm_RJySaBQTL3B3EDD6swPrRFNZBXUtW9CdFRFLaEJoMqIevf2DrnRnWj-eiDiPyYgTEv1LsYRRPOIceyrcU8poaw0UR8sEi22y4iRZz9_8nvNI_-RIvwER2J_M</recordid><startdate>20210127</startdate><enddate>20210127</enddate><creator>Creamer, Tyler J</creator><creator>Bramel, Emily E</creator><creator>MacFarlane, Elena Gallo</creator><general>MDPI AG</general><general>MDPI</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>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-1872-5248</orcidid></search><sort><creationdate>20210127</creationdate><title>Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies</title><author>Creamer, Tyler J ; Bramel, Emily E ; MacFarlane, Elena Gallo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-c48005db3b4db30e3b7e0f7a591f15073ba4f594eafce5d0c9f7ca9d35a307ac3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Actin</topic><topic>Adaptation, Physiological</topic><topic>Alleles</topic><topic>Aneurysms</topic><topic>Animals</topic><topic>Aorta</topic><topic>Aortic Aneurysm, Thoracic - diagnosis</topic><topic>Aortic Aneurysm, Thoracic - genetics</topic><topic>Aortic Aneurysm, Thoracic - metabolism</topic><topic>Aortic Aneurysm, Thoracic - therapy</topic><topic>Aortic aneurysms</topic><topic>Biomarkers</topic><topic>Clinical Decision-Making</topic><topic>Collagen</topic><topic>Coronary vessels</topic><topic>Cytoskeleton</topic><topic>Degeneration</topic><topic>Disease Management</topic><topic>Dissection</topic><topic>Extracellular matrix</topic><topic>Extracellular Matrix - genetics</topic><topic>Fibroblasts</topic><topic>Genetic Association Studies - methods</topic><topic>Genetic Predisposition to Disease</topic><topic>Genotype</topic><topic>Genotype & phenotype</topic><topic>Growth factors</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Integrins</topic><topic>Ligands</topic><topic>Muscle, Smooth, Vascular - metabolism</topic><topic>Mutation</topic><topic>Myocytes, Smooth Muscle - metabolism</topic><topic>Myosin</topic><topic>Pathogenesis</topic><topic>Phenotype</topic><topic>Phenotypes</topic><topic>Physiology</topic><topic>Proteins</topic><topic>Review</topic><topic>Signal Transduction</topic><topic>Smooth muscle</topic><topic>Thorax</topic><topic>Transforming growth factor-b</topic><topic>Veins & arteries</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Creamer, Tyler J</creatorcontrib><creatorcontrib>Bramel, Emily E</creatorcontrib><creatorcontrib>MacFarlane, Elena Gallo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Genes</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Creamer, Tyler J</au><au>Bramel, Emily E</au><au>MacFarlane, Elena Gallo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies</atitle><jtitle>Genes</jtitle><addtitle>Genes (Basel)</addtitle><date>2021-01-27</date><risdate>2021</risdate><volume>12</volume><issue>2</issue><spage>183</spage><pages>183-</pages><issn>2073-4425</issn><eissn>2073-4425</eissn><abstract>Thoracic aortic aneurysms (TAA) are permanent and localized dilations of the aorta that predispose patients to a life-threatening risk of aortic dissection or rupture. The identification of pathogenic variants that cause hereditary forms of TAA has delineated fundamental molecular processes required to maintain aortic homeostasis. Vascular smooth muscle cells (VSMCs) elaborate and remodel the extracellular matrix (ECM) in response to mechanical and biochemical cues from their environment. Causal variants for hereditary forms of aneurysm compromise the function of gene products involved in the transmission or interpretation of these signals, initiating processes that eventually lead to degeneration and mechanical failure of the vessel. These include mutations that interfere with transduction of stimuli from the matrix to the actin-myosin cytoskeleton through integrins, and those that impair signaling pathways activated by transforming growth factor-β (TGF-β). In this review, we summarize the features of the healthy aortic wall, the major pathways involved in the modulation of VSMC phenotypes, and the basic molecular functions impaired by TAA-associated mutations. We also discuss how the heterogeneity and balance of adaptive and maladaptive responses to the initial genetic insult might contribute to disease.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>33514025</pmid><doi>10.3390/genes12020183</doi><orcidid>https://orcid.org/0000-0003-1872-5248</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Actin Adaptation, Physiological Alleles Aneurysms Animals Aorta Aortic Aneurysm, Thoracic - diagnosis Aortic Aneurysm, Thoracic - genetics Aortic Aneurysm, Thoracic - metabolism Aortic Aneurysm, Thoracic - therapy Aortic aneurysms Biomarkers Clinical Decision-Making Collagen Coronary vessels Cytoskeleton Degeneration Disease Management Dissection Extracellular matrix Extracellular Matrix - genetics Fibroblasts Genetic Association Studies - methods Genetic Predisposition to Disease Genotype Genotype & phenotype Growth factors Homeostasis Humans Integrins Ligands Muscle, Smooth, Vascular - metabolism Mutation Myocytes, Smooth Muscle - metabolism Myosin Pathogenesis Phenotype Phenotypes Physiology Proteins Review Signal Transduction Smooth muscle Thorax Transforming growth factor-b Veins & arteries |
title | Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies |
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