Cellular Senescence Contributes to Large Elastic Artery Stiffening and Endothelial Dysfunction With Aging: Amelioration With Senolytic Treatment
Here, we assessed the role of cellular senescence and the senescence associated secretory phenotype (SASP) in age-related aortic stiffening and endothelial dysfunction. We studied young (6-8 mo) and old (27-29 mo) p16-3MR mice, which allows for genetic-based clearance of senescent cells with gancicl...
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| Veröffentlicht in: | Hypertension (Dallas, Tex. 1979) Tex. 1979), 2023-10, Vol.80 (10), p.2072-2087 |
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| creator | Clayton, Zachary S Rossman, Matthew J Mahoney, Sophia A Venkatasubramanian, Ravinandan Maurer, Grace S Hutton, David A VanDongen, Nicholas S Greenberg, Nathan T Longtine, Abigail G Ludwig, Katelyn R Brunt, Vienna E LaRocca, Thomas J Campisi, Judith Melov, Simon Seals, Douglas R |
| description | Here, we assessed the role of cellular senescence and the senescence associated secretory phenotype (SASP) in age-related aortic stiffening and endothelial dysfunction.
We studied young (6-8 mo) and old (27-29 mo) p16-3MR mice, which allows for genetic-based clearance of senescent cells with ganciclovir (GCV). We also treated old C57BL/6N mice with the senolytic ABT-263.
In old mice, GCV reduced aortic stiffness assessed by aortic pulse wave velocity (PWV; 477±10 vs. 382±7 cm/s, |
| doi_str_mv | 10.1161/HYPERTENSIONAHA.123.21392 |
| format | Article |
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We studied young (6-8 mo) and old (27-29 mo) p16-3MR mice, which allows for genetic-based clearance of senescent cells with ganciclovir (GCV). We also treated old C57BL/6N mice with the senolytic ABT-263.
In old mice, GCV reduced aortic stiffness assessed by aortic pulse wave velocity (PWV; 477±10 vs. 382±7 cm/s,
<0.05) to young levels (old-GCV vs. young-vehicle,
=0.35); ABT-263 also reduced aortic PWV in old mice (446±9 to 356±11 cm/s,
<0.05). Aortic adventitial collagen was reduced by GCV (
<0.05) and ABT-263 (
=0.12) in old mice. To show an effect of the circulating SASP, we demonstrated that plasma exposure from Old-vehicle p16-3MR mice, but not from Old-GCV mice, induced aortic stiffening assessed
(elastic modulus;
<0.05). Plasma proteomics implicated glycolysis in circulating SASP-mediated aortic stiffening. In old p16-3MR mice, GCV increased endothelial function assessed via peak carotid artery endothelium-dependent dilation (EDD; Old-GCV, 94±1% vs. Old-vehicle, 84±2%,
<0.05) to young levels (Old-GCV vs. young-vehicle,
=0.98), and EDD was higher in old C57BL/6N mice treated with ABT-263 vs. vehicle (96±1% vs. 82±3%,
<0.05). Improvements in endothelial function were mediated by increased nitric oxide (NO) bioavailability (
<0.05) and reduced oxidative stress (
<0.05). Circulating SASP factors related to NO signaling were associated with greater NO-mediated EDD following senescent cell clearance.
Cellular senescence and the SASP contribute to vascular aging and senolytics hold promise for improving age-related vascular function.]]></description><identifier>ISSN: 0194-911X</identifier><identifier>ISSN: 1524-4563</identifier><identifier>EISSN: 1524-4563</identifier><identifier>DOI: 10.1161/HYPERTENSIONAHA.123.21392</identifier><identifier>PMID: 37593877</identifier><language>eng</language><publisher>United States</publisher><subject>Aging ; Animals ; Arteries ; Cellular Senescence ; Mice ; Mice, Inbred C57BL ; Nitric Oxide ; Pulse Wave Analysis ; Senotherapeutics ; Vascular Diseases</subject><ispartof>Hypertension (Dallas, Tex. 1979), 2023-10, Vol.80 (10), p.2072-2087</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c373t-f55c47f722c990cb979e81393902e0851d6212e71ff930dc2c1430b541dc054e3</citedby><cites>FETCH-LOGICAL-c373t-f55c47f722c990cb979e81393902e0851d6212e71ff930dc2c1430b541dc054e3</cites><orcidid>0000-0001-6858-9462 ; 0000-0001-7905-8341 ; 0000-0001-8554-2834 ; 0000-0003-3878-3533 ; 0000-0002-2391-9824 ; 0000-0002-5827-6953 ; 0000-0001-9381-2590 ; 0000-0002-1941-7936 ; 0000-0002-0013-4514</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,3688,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37593877$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Clayton, Zachary S</creatorcontrib><creatorcontrib>Rossman, Matthew J</creatorcontrib><creatorcontrib>Mahoney, Sophia A</creatorcontrib><creatorcontrib>Venkatasubramanian, Ravinandan</creatorcontrib><creatorcontrib>Maurer, Grace S</creatorcontrib><creatorcontrib>Hutton, David A</creatorcontrib><creatorcontrib>VanDongen, Nicholas S</creatorcontrib><creatorcontrib>Greenberg, Nathan T</creatorcontrib><creatorcontrib>Longtine, Abigail G</creatorcontrib><creatorcontrib>Ludwig, Katelyn R</creatorcontrib><creatorcontrib>Brunt, Vienna E</creatorcontrib><creatorcontrib>LaRocca, Thomas J</creatorcontrib><creatorcontrib>Campisi, Judith</creatorcontrib><creatorcontrib>Melov, Simon</creatorcontrib><creatorcontrib>Seals, Douglas R</creatorcontrib><title>Cellular Senescence Contributes to Large Elastic Artery Stiffening and Endothelial Dysfunction With Aging: Amelioration With Senolytic Treatment</title><title>Hypertension (Dallas, Tex. 1979)</title><addtitle>Hypertension</addtitle><description><![CDATA[Here, we assessed the role of cellular senescence and the senescence associated secretory phenotype (SASP) in age-related aortic stiffening and endothelial dysfunction.
We studied young (6-8 mo) and old (27-29 mo) p16-3MR mice, which allows for genetic-based clearance of senescent cells with ganciclovir (GCV). We also treated old C57BL/6N mice with the senolytic ABT-263.
In old mice, GCV reduced aortic stiffness assessed by aortic pulse wave velocity (PWV; 477±10 vs. 382±7 cm/s,
<0.05) to young levels (old-GCV vs. young-vehicle,
=0.35); ABT-263 also reduced aortic PWV in old mice (446±9 to 356±11 cm/s,
<0.05). Aortic adventitial collagen was reduced by GCV (
<0.05) and ABT-263 (
=0.12) in old mice. To show an effect of the circulating SASP, we demonstrated that plasma exposure from Old-vehicle p16-3MR mice, but not from Old-GCV mice, induced aortic stiffening assessed
(elastic modulus;
<0.05). Plasma proteomics implicated glycolysis in circulating SASP-mediated aortic stiffening. In old p16-3MR mice, GCV increased endothelial function assessed via peak carotid artery endothelium-dependent dilation (EDD; Old-GCV, 94±1% vs. Old-vehicle, 84±2%,
<0.05) to young levels (Old-GCV vs. young-vehicle,
=0.98), and EDD was higher in old C57BL/6N mice treated with ABT-263 vs. vehicle (96±1% vs. 82±3%,
<0.05). Improvements in endothelial function were mediated by increased nitric oxide (NO) bioavailability (
<0.05) and reduced oxidative stress (
<0.05). Circulating SASP factors related to NO signaling were associated with greater NO-mediated EDD following senescent cell clearance.
Cellular senescence and the SASP contribute to vascular aging and senolytics hold promise for improving age-related vascular function.]]></description><subject>Aging</subject><subject>Animals</subject><subject>Arteries</subject><subject>Cellular Senescence</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Nitric Oxide</subject><subject>Pulse Wave Analysis</subject><subject>Senotherapeutics</subject><subject>Vascular Diseases</subject><issn>0194-911X</issn><issn>1524-4563</issn><issn>1524-4563</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkd2O0zAQhSMEYsvCKyBzx02K_9LE3KCoBLpStYtoEXBluc6kNXLsXdtB6lvwyLjssvxII83FOXPGnq8oXhA8J2RBXq2-fug-brvLzcXVZbtq54SyOSVM0AfFjFSUl7xasIfFDBPBS0HIl7PiSYzfMCac8_pxccbqSrCmrmfFjyVYO1kV0AYcRA1OA1p6l4LZTQkiSh6tVdgD6qyKyWjUhgThiDbJDAM44_ZIuR51rvfpANYoi94e4zA5nYx36LNJB9Tus-01ases-6D-CHmnt8dT6jaASiO49LR4NCgb4dldPy8-veu2y1W5vnp_sWzXpWY1S-VQVZrXQ02pFgLrnagFNPkETGAKuKlIv6CEQk2GQTDca6oJZ3hXcdJrXHFg58Wb29zraTdCnz-egrLyOphRhaP0ysh_FWcOcu-_S4IrlqvJCS_vEoK_mSAmOZp8QGuVAz9FSZuKiUyCn6zi1qqDjzHAcL-HYHlCKv9DKjNS-Qtpnn3-90PvJ38zZD8Bv0aigQ</recordid><startdate>20231001</startdate><enddate>20231001</enddate><creator>Clayton, Zachary S</creator><creator>Rossman, Matthew J</creator><creator>Mahoney, Sophia A</creator><creator>Venkatasubramanian, Ravinandan</creator><creator>Maurer, Grace S</creator><creator>Hutton, David A</creator><creator>VanDongen, Nicholas S</creator><creator>Greenberg, Nathan T</creator><creator>Longtine, Abigail G</creator><creator>Ludwig, Katelyn R</creator><creator>Brunt, Vienna E</creator><creator>LaRocca, Thomas J</creator><creator>Campisi, Judith</creator><creator>Melov, Simon</creator><creator>Seals, Douglas R</creator><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><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6858-9462</orcidid><orcidid>https://orcid.org/0000-0001-7905-8341</orcidid><orcidid>https://orcid.org/0000-0001-8554-2834</orcidid><orcidid>https://orcid.org/0000-0003-3878-3533</orcidid><orcidid>https://orcid.org/0000-0002-2391-9824</orcidid><orcidid>https://orcid.org/0000-0002-5827-6953</orcidid><orcidid>https://orcid.org/0000-0001-9381-2590</orcidid><orcidid>https://orcid.org/0000-0002-1941-7936</orcidid><orcidid>https://orcid.org/0000-0002-0013-4514</orcidid></search><sort><creationdate>20231001</creationdate><title>Cellular Senescence Contributes to Large Elastic Artery Stiffening and Endothelial Dysfunction With Aging: Amelioration With Senolytic Treatment</title><author>Clayton, Zachary S ; Rossman, Matthew J ; Mahoney, Sophia A ; Venkatasubramanian, Ravinandan ; Maurer, Grace S ; Hutton, David A ; VanDongen, Nicholas S ; Greenberg, Nathan T ; Longtine, Abigail G ; Ludwig, Katelyn R ; Brunt, Vienna E ; LaRocca, Thomas J ; Campisi, Judith ; Melov, Simon ; Seals, Douglas R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c373t-f55c47f722c990cb979e81393902e0851d6212e71ff930dc2c1430b541dc054e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Aging</topic><topic>Animals</topic><topic>Arteries</topic><topic>Cellular Senescence</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Nitric Oxide</topic><topic>Pulse Wave Analysis</topic><topic>Senotherapeutics</topic><topic>Vascular Diseases</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Clayton, Zachary S</creatorcontrib><creatorcontrib>Rossman, Matthew J</creatorcontrib><creatorcontrib>Mahoney, Sophia A</creatorcontrib><creatorcontrib>Venkatasubramanian, Ravinandan</creatorcontrib><creatorcontrib>Maurer, Grace S</creatorcontrib><creatorcontrib>Hutton, David A</creatorcontrib><creatorcontrib>VanDongen, Nicholas S</creatorcontrib><creatorcontrib>Greenberg, Nathan T</creatorcontrib><creatorcontrib>Longtine, Abigail G</creatorcontrib><creatorcontrib>Ludwig, Katelyn R</creatorcontrib><creatorcontrib>Brunt, Vienna E</creatorcontrib><creatorcontrib>LaRocca, Thomas J</creatorcontrib><creatorcontrib>Campisi, Judith</creatorcontrib><creatorcontrib>Melov, Simon</creatorcontrib><creatorcontrib>Seals, Douglas R</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Hypertension (Dallas, Tex. 1979)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Clayton, Zachary S</au><au>Rossman, Matthew J</au><au>Mahoney, Sophia A</au><au>Venkatasubramanian, Ravinandan</au><au>Maurer, Grace S</au><au>Hutton, David A</au><au>VanDongen, Nicholas S</au><au>Greenberg, Nathan T</au><au>Longtine, Abigail G</au><au>Ludwig, Katelyn R</au><au>Brunt, Vienna E</au><au>LaRocca, Thomas J</au><au>Campisi, Judith</au><au>Melov, Simon</au><au>Seals, Douglas R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cellular Senescence Contributes to Large Elastic Artery Stiffening and Endothelial Dysfunction With Aging: Amelioration With Senolytic Treatment</atitle><jtitle>Hypertension (Dallas, Tex. 1979)</jtitle><addtitle>Hypertension</addtitle><date>2023-10-01</date><risdate>2023</risdate><volume>80</volume><issue>10</issue><spage>2072</spage><epage>2087</epage><pages>2072-2087</pages><issn>0194-911X</issn><issn>1524-4563</issn><eissn>1524-4563</eissn><abstract><![CDATA[Here, we assessed the role of cellular senescence and the senescence associated secretory phenotype (SASP) in age-related aortic stiffening and endothelial dysfunction.
We studied young (6-8 mo) and old (27-29 mo) p16-3MR mice, which allows for genetic-based clearance of senescent cells with ganciclovir (GCV). We also treated old C57BL/6N mice with the senolytic ABT-263.
In old mice, GCV reduced aortic stiffness assessed by aortic pulse wave velocity (PWV; 477±10 vs. 382±7 cm/s,
<0.05) to young levels (old-GCV vs. young-vehicle,
=0.35); ABT-263 also reduced aortic PWV in old mice (446±9 to 356±11 cm/s,
<0.05). Aortic adventitial collagen was reduced by GCV (
<0.05) and ABT-263 (
=0.12) in old mice. To show an effect of the circulating SASP, we demonstrated that plasma exposure from Old-vehicle p16-3MR mice, but not from Old-GCV mice, induced aortic stiffening assessed
(elastic modulus;
<0.05). Plasma proteomics implicated glycolysis in circulating SASP-mediated aortic stiffening. In old p16-3MR mice, GCV increased endothelial function assessed via peak carotid artery endothelium-dependent dilation (EDD; Old-GCV, 94±1% vs. Old-vehicle, 84±2%,
<0.05) to young levels (Old-GCV vs. young-vehicle,
=0.98), and EDD was higher in old C57BL/6N mice treated with ABT-263 vs. vehicle (96±1% vs. 82±3%,
<0.05). Improvements in endothelial function were mediated by increased nitric oxide (NO) bioavailability (
<0.05) and reduced oxidative stress (
<0.05). Circulating SASP factors related to NO signaling were associated with greater NO-mediated EDD following senescent cell clearance.
Cellular senescence and the SASP contribute to vascular aging and senolytics hold promise for improving age-related vascular function.]]></abstract><cop>United States</cop><pmid>37593877</pmid><doi>10.1161/HYPERTENSIONAHA.123.21392</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0001-6858-9462</orcidid><orcidid>https://orcid.org/0000-0001-7905-8341</orcidid><orcidid>https://orcid.org/0000-0001-8554-2834</orcidid><orcidid>https://orcid.org/0000-0003-3878-3533</orcidid><orcidid>https://orcid.org/0000-0002-2391-9824</orcidid><orcidid>https://orcid.org/0000-0002-5827-6953</orcidid><orcidid>https://orcid.org/0000-0001-9381-2590</orcidid><orcidid>https://orcid.org/0000-0002-1941-7936</orcidid><orcidid>https://orcid.org/0000-0002-0013-4514</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0194-911X |
| ispartof | Hypertension (Dallas, Tex. 1979), 2023-10, Vol.80 (10), p.2072-2087 |
| issn | 0194-911X 1524-4563 1524-4563 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10530538 |
| source | MEDLINE; American Heart Association Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Aging Animals Arteries Cellular Senescence Mice Mice, Inbred C57BL Nitric Oxide Pulse Wave Analysis Senotherapeutics Vascular Diseases |
| title | Cellular Senescence Contributes to Large Elastic Artery Stiffening and Endothelial Dysfunction With Aging: Amelioration With Senolytic Treatment |
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