Reduced caveolae density in arteries of SHR contributes to endothelial dysfunction and ROS production
Autor(a) principal: | |
---|---|
Data de Publicação: | 2019 |
Outros Autores: | , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1038/s41598-019-43193-8 http://hdl.handle.net/11449/184465 |
Resumo: | Caveolae are plasma membrane invaginations enriched with high cholesterol and sphingolipid content; they also contain caveolin proteins in their structure. Endothelial nitric oxide synthase (eNOS), an enzyme that synthesizes nitric oxide (NO) by converting L-arginine to L-citrulline, is highly concentrated in plasma membrane caveolae. Hypertension is associated with decreased NO production and impaired endothelium-dependent relaxation. Understanding the molecular mechanisms that follow hypertension is important. For this study, we hypothesized that spontaneously hypertensive rat (SHR) vessels should have a smaller number of caveolae, and that the caveolae structure should be disrupted in these vessels. This should impair the eNOS function and diminish NO bioavailability. Therefore, we aimed to investigate caveolae integrity and density in SHR aortas and mesenteric arteries and the role played by caveolae in endothelium-dependent relaxation. We have been able to show the presence of caveolae-like structures in SHR aortas and mesenteric arteries. Increased phenylephrine-induced contractile response after treatment with dextrin was related to lower NO release. In addition, impaired acetylcholine-induced endothelium-dependent relaxation could be related to decreased caveolae density in SHR vessels. The most important finding of this study was that cholesterol depletion with dextrin induced eNOS phosphorylation at Serine(1177) (Ser(1177)) and boosted reactive oxygen species (ROS) production in normotensive rat and SHR vessels, which suggested eNOS uncoupling. Dextrin plus L-NAME or BH4 decreased ROS production in aorta and mesenteric arteries supernatant's of both SHR and normotensive groups. Human umbilical vein endothelial cells (HUVECs) treated with dextrin confirmed eNOS uncoupling, as verified by the reduced eNOS dimer/monomer ratio. BH4, L-arginine, or BH4 plus L-arginine inhibited eNOS monomerization. All these results showed that caveolae structure and integrity are essential for endothelium-dependent relaxation. Additionally, a smaller number of caveolae is associated with hypertension. Finally, caveolae disruption promotes eNOS uncoupling in normotensive and hypertensive rat vessels and in HUVECs. |
id |
UNSP_9cb0dc4fc51528f668d7647485462ff8 |
---|---|
oai_identifier_str |
oai:repositorio.unesp.br:11449/184465 |
network_acronym_str |
UNSP |
network_name_str |
Repositório Institucional da UNESP |
repository_id_str |
2946 |
spelling |
Reduced caveolae density in arteries of SHR contributes to endothelial dysfunction and ROS productionCaveolae are plasma membrane invaginations enriched with high cholesterol and sphingolipid content; they also contain caveolin proteins in their structure. Endothelial nitric oxide synthase (eNOS), an enzyme that synthesizes nitric oxide (NO) by converting L-arginine to L-citrulline, is highly concentrated in plasma membrane caveolae. Hypertension is associated with decreased NO production and impaired endothelium-dependent relaxation. Understanding the molecular mechanisms that follow hypertension is important. For this study, we hypothesized that spontaneously hypertensive rat (SHR) vessels should have a smaller number of caveolae, and that the caveolae structure should be disrupted in these vessels. This should impair the eNOS function and diminish NO bioavailability. Therefore, we aimed to investigate caveolae integrity and density in SHR aortas and mesenteric arteries and the role played by caveolae in endothelium-dependent relaxation. We have been able to show the presence of caveolae-like structures in SHR aortas and mesenteric arteries. Increased phenylephrine-induced contractile response after treatment with dextrin was related to lower NO release. In addition, impaired acetylcholine-induced endothelium-dependent relaxation could be related to decreased caveolae density in SHR vessels. The most important finding of this study was that cholesterol depletion with dextrin induced eNOS phosphorylation at Serine(1177) (Ser(1177)) and boosted reactive oxygen species (ROS) production in normotensive rat and SHR vessels, which suggested eNOS uncoupling. Dextrin plus L-NAME or BH4 decreased ROS production in aorta and mesenteric arteries supernatant's of both SHR and normotensive groups. Human umbilical vein endothelial cells (HUVECs) treated with dextrin confirmed eNOS uncoupling, as verified by the reduced eNOS dimer/monomer ratio. BH4, L-arginine, or BH4 plus L-arginine inhibited eNOS monomerization. All these results showed that caveolae structure and integrity are essential for endothelium-dependent relaxation. Additionally, a smaller number of caveolae is associated with hypertension. Finally, caveolae disruption promotes eNOS uncoupling in normotensive and hypertensive rat vessels and in HUVECs.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ Sao Paulo, Dept Phys & Chem, Fac Pharmaceut Sci Ribeirao Preto, Sao Paulo, BrazilUniv Arizona, Coll Med, Dept Anesthesiol, Tucson, AZ USAState Univ Sao Paulo, Dept Basic Sci, Sch Dent, Sao Paulo, BrazilState Univ Sao Paulo, Dept Basic Sci, Sch Dent, Sao Paulo, BrazilFAPESP: 2016/22180-9FAPESP: 2016/21239-0FAPESP: 2017/14797-9CNPq: 400.164/2014-0CNPq: 304.137/2014-6Nature Publishing GroupUniversidade de São Paulo (USP)Univ ArizonaUniversidade Estadual Paulista (Unesp)Potje, Simone R.Grando, Marcella D.Chignalia, Andreia Z.Antoniali, Cristina [UNESP]Bendhack, Lusiane M.2019-10-04T12:13:45Z2019-10-04T12:13:45Z2019-04-30info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article16http://dx.doi.org/10.1038/s41598-019-43193-8Scientific Reports. London: Nature Publishing Group, v. 9, 16 p., 2019.2045-2322http://hdl.handle.net/11449/18446510.1038/s41598-019-43193-8WOS:000466351100055Web of Sciencereponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengScientific Reportsinfo:eu-repo/semantics/openAccess2021-10-22T21:54:14Zoai:repositorio.unesp.br:11449/184465Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T23:15:23.565398Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Reduced caveolae density in arteries of SHR contributes to endothelial dysfunction and ROS production |
title |
Reduced caveolae density in arteries of SHR contributes to endothelial dysfunction and ROS production |
spellingShingle |
Reduced caveolae density in arteries of SHR contributes to endothelial dysfunction and ROS production Potje, Simone R. |
title_short |
Reduced caveolae density in arteries of SHR contributes to endothelial dysfunction and ROS production |
title_full |
Reduced caveolae density in arteries of SHR contributes to endothelial dysfunction and ROS production |
title_fullStr |
Reduced caveolae density in arteries of SHR contributes to endothelial dysfunction and ROS production |
title_full_unstemmed |
Reduced caveolae density in arteries of SHR contributes to endothelial dysfunction and ROS production |
title_sort |
Reduced caveolae density in arteries of SHR contributes to endothelial dysfunction and ROS production |
author |
Potje, Simone R. |
author_facet |
Potje, Simone R. Grando, Marcella D. Chignalia, Andreia Z. Antoniali, Cristina [UNESP] Bendhack, Lusiane M. |
author_role |
author |
author2 |
Grando, Marcella D. Chignalia, Andreia Z. Antoniali, Cristina [UNESP] Bendhack, Lusiane M. |
author2_role |
author author author author |
dc.contributor.none.fl_str_mv |
Universidade de São Paulo (USP) Univ Arizona Universidade Estadual Paulista (Unesp) |
dc.contributor.author.fl_str_mv |
Potje, Simone R. Grando, Marcella D. Chignalia, Andreia Z. Antoniali, Cristina [UNESP] Bendhack, Lusiane M. |
description |
Caveolae are plasma membrane invaginations enriched with high cholesterol and sphingolipid content; they also contain caveolin proteins in their structure. Endothelial nitric oxide synthase (eNOS), an enzyme that synthesizes nitric oxide (NO) by converting L-arginine to L-citrulline, is highly concentrated in plasma membrane caveolae. Hypertension is associated with decreased NO production and impaired endothelium-dependent relaxation. Understanding the molecular mechanisms that follow hypertension is important. For this study, we hypothesized that spontaneously hypertensive rat (SHR) vessels should have a smaller number of caveolae, and that the caveolae structure should be disrupted in these vessels. This should impair the eNOS function and diminish NO bioavailability. Therefore, we aimed to investigate caveolae integrity and density in SHR aortas and mesenteric arteries and the role played by caveolae in endothelium-dependent relaxation. We have been able to show the presence of caveolae-like structures in SHR aortas and mesenteric arteries. Increased phenylephrine-induced contractile response after treatment with dextrin was related to lower NO release. In addition, impaired acetylcholine-induced endothelium-dependent relaxation could be related to decreased caveolae density in SHR vessels. The most important finding of this study was that cholesterol depletion with dextrin induced eNOS phosphorylation at Serine(1177) (Ser(1177)) and boosted reactive oxygen species (ROS) production in normotensive rat and SHR vessels, which suggested eNOS uncoupling. Dextrin plus L-NAME or BH4 decreased ROS production in aorta and mesenteric arteries supernatant's of both SHR and normotensive groups. Human umbilical vein endothelial cells (HUVECs) treated with dextrin confirmed eNOS uncoupling, as verified by the reduced eNOS dimer/monomer ratio. BH4, L-arginine, or BH4 plus L-arginine inhibited eNOS monomerization. All these results showed that caveolae structure and integrity are essential for endothelium-dependent relaxation. Additionally, a smaller number of caveolae is associated with hypertension. Finally, caveolae disruption promotes eNOS uncoupling in normotensive and hypertensive rat vessels and in HUVECs. |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019-10-04T12:13:45Z 2019-10-04T12:13:45Z 2019-04-30 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1038/s41598-019-43193-8 Scientific Reports. London: Nature Publishing Group, v. 9, 16 p., 2019. 2045-2322 http://hdl.handle.net/11449/184465 10.1038/s41598-019-43193-8 WOS:000466351100055 |
url |
http://dx.doi.org/10.1038/s41598-019-43193-8 http://hdl.handle.net/11449/184465 |
identifier_str_mv |
Scientific Reports. London: Nature Publishing Group, v. 9, 16 p., 2019. 2045-2322 10.1038/s41598-019-43193-8 WOS:000466351100055 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Scientific Reports |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
16 |
dc.publisher.none.fl_str_mv |
Nature Publishing Group |
publisher.none.fl_str_mv |
Nature Publishing Group |
dc.source.none.fl_str_mv |
Web of Science reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
_version_ |
1808129502763548672 |