Serotonin 3 receptor antagonism reduces angiotensin II–induced abdominal aortic aneurysms: Contribution of periaortic fat–derived serotonin

Yasir AlSiraj; Charles M. Ensor; Victoria English; Analia Loria; Heba Ali; Lisa A. Cassis

doi:10.1016/j.jpet.2024.100533

Serotonin 3 receptor antagonism reduces angiotensin II–induced abdominal aortic aneurysms: Contribution of periaortic fat–derived serotonin

Yasir AlSiraj
, Charles M. Ensor
, Victoria English
, Analia Loria
, Heba Ali
, Lisa A. Cassis

Research output: Contribution to journal › Article › peer-review

Abstract

Serotonin (5-HT) has been implicated in cerebral aneurysm rupture, but it is unclear whether 5-HT plays a role in aortic aneurysm development and rupture, despite well known contractile effects of 5-HT through aortic 5-HT receptors. Abdominal aortic aneurysms (AAAs) induced by angiotensin II (AngII) infusion to mice exhibit periaortic inflammation and are prone to rupture. Periaortic fat (PAF), a potential source of 5-HT through tryptophan hydroxylase 1 (Tph1), has been implicated in AAA development. We quantified mRNA abundance of 5-HT receptors (Htr1b, Htr2a, Htr2b, Htr3a, and Htr7) and Tph1 in thoracic and abdominal aortas and surrounding PAF. Compared with other 5-HT receptors, we detected high levels of serotonin 3 receptor type a (Htr3a) mRNA in the abdominal aortas and abdominal PAF. Tph1 mRNA and 5-HT immunostaining were detected in aortas and PAF, with 5-HT levels higher in abdominal than thoracic PAF, and higher in epididymal white than interscapular brown fat. AngII infusion facilitated evoked [³H]5-HT release from thoracic PAF and modestly reduced 5-HT levels in thoracic PAF and brown fat. Based on a high level of Htr3a mRNA in abdominal aortas and PAF, we investigated the development of AngII-induced AAAs when serotonin 3 receptors were pharmacologically antagonized with tropisetron. Tropisetron abrogated abdominal aortic lumen diameters, aneurysm (distal thoracic aneurysm and AAA) incidence, maximal AAA diameters, and aortic weights of AngII-infused male mice. These findings indicate a novel role for serotonin 3 receptor in AAA development, with a potential clinically relevant contribution for PAF as a local source of 5-HT. Significance Statement: Aortic aneurysms are life-threatening vascular disorders with no effective therapeutics. This study identified antagonism of the serotonin 3 receptor as a potential therapeutic target to reduce the formation and severity of experimentally-induced aneurysms in the thoracic and abdominal aorta. Additionally, periaortic fat was identified as a potential site for serotonin production in the development of aortic aneurysms.

Original language	English
Article number	100533
Journal	Journal of Pharmacology and Experimental Therapeutics
Volume	392
Issue number	2
DOIs	https://doi.org/10.1016/j.jpet.2024.100533
State	Published - Feb 2025

Bibliographical note

Publisher Copyright:
© 2024 The Authors

Funding

We acknowledge the use of research cores within the National Institutes of Health Center of Biomedical Excellence on Obesity and Cardiovascular Diseases (GM127211, L.A.C.). This study was supported by the National Institutes of Health Heart, Lung and Blood Institute (R01 HL168633 to L.A.C.) and General Medical Sciences (NIH IDeA program, GM127211 to L.A.C.). The data that support the findings of this study are available in the Electronic Laboratory Notebook maintained by the University of Kentucky and are available upon request of the author. All other data presented are contained within the article/supplemental material. Participated in research design: AlSiraj, Ensor, Loria, Cassis. Conducted experiments: AlSiraj, Ensor, English, Ali. Performed data analysis: AlSiraj, Ensor, Cassis. Wrote or contributed to the writing of the manuscript: AlSiraj, Ensor, Loria, Cassis. These studies were supported by the National Institutes of Health Heart, Lung and Blood Institute and General Medical Sciences (NIH IDeA program) R01 HL168633 (LAC). We also acknowledge use of research cores within the NIH Center of Biomedical Excellence on Obesity and Cardiovascular Diseases (GM127211, LAC).

Funders	Funder number
University of Kentucky
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences
National Institutes of Health Center of Biomedical Excellence on Obesity and Cardiovascular Diseases	GM127211
National Institutes of Health National Heart, Lung, and Blood Institute	R01 HL168633
National Institutes of Health (NIH)	R01 HL168633
National Institutes of Health (NIH)

Keywords

Angiotensin
Aortic aneurysm
Periaortic fat
Serotonin
Serotonin 3 receptors

ASJC Scopus subject areas

Molecular Medicine
Pharmacology

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10.1016/j.jpet.2024.100533

Cite this

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title = "Serotonin 3 receptor antagonism reduces angiotensin II–induced abdominal aortic aneurysms: Contribution of periaortic fat–derived serotonin",

abstract = "Serotonin (5-HT) has been implicated in cerebral aneurysm rupture, but it is unclear whether 5-HT plays a role in aortic aneurysm development and rupture, despite well known contractile effects of 5-HT through aortic 5-HT receptors. Abdominal aortic aneurysms (AAAs) induced by angiotensin II (AngII) infusion to mice exhibit periaortic inflammation and are prone to rupture. Periaortic fat (PAF), a potential source of 5-HT through tryptophan hydroxylase 1 (Tph1), has been implicated in AAA development. We quantified mRNA abundance of 5-HT receptors (Htr1b, Htr2a, Htr2b, Htr3a, and Htr7) and Tph1 in thoracic and abdominal aortas and surrounding PAF. Compared with other 5-HT receptors, we detected high levels of serotonin 3 receptor type a (Htr3a) mRNA in the abdominal aortas and abdominal PAF. Tph1 mRNA and 5-HT immunostaining were detected in aortas and PAF, with 5-HT levels higher in abdominal than thoracic PAF, and higher in epididymal white than interscapular brown fat. AngII infusion facilitated evoked [3H]5-HT release from thoracic PAF and modestly reduced 5-HT levels in thoracic PAF and brown fat. Based on a high level of Htr3a mRNA in abdominal aortas and PAF, we investigated the development of AngII-induced AAAs when serotonin 3 receptors were pharmacologically antagonized with tropisetron. Tropisetron abrogated abdominal aortic lumen diameters, aneurysm (distal thoracic aneurysm and AAA) incidence, maximal AAA diameters, and aortic weights of AngII-infused male mice. These findings indicate a novel role for serotonin 3 receptor in AAA development, with a potential clinically relevant contribution for PAF as a local source of 5-HT. Significance Statement: Aortic aneurysms are life-threatening vascular disorders with no effective therapeutics. This study identified antagonism of the serotonin 3 receptor as a potential therapeutic target to reduce the formation and severity of experimentally-induced aneurysms in the thoracic and abdominal aorta. Additionally, periaortic fat was identified as a potential site for serotonin production in the development of aortic aneurysms.",

keywords = "Angiotensin, Aortic aneurysm, Periaortic fat, Serotonin, Serotonin 3 receptors",

author = "Yasir AlSiraj and Ensor, \{Charles M.\} and Victoria English and Analia Loria and Heba Ali and Cassis, \{Lisa A.\}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2025",

month = feb,

doi = "10.1016/j.jpet.2024.100533",

language = "English",

volume = "392",

number = "2",

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TY - JOUR

T1 - Serotonin 3 receptor antagonism reduces angiotensin II–induced abdominal aortic aneurysms

T2 - Contribution of periaortic fat–derived serotonin

AU - AlSiraj, Yasir

AU - Ensor, Charles M.

AU - English, Victoria

AU - Loria, Analia

AU - Ali, Heba

AU - Cassis, Lisa A.

PY - 2025/2

Y1 - 2025/2

N2 - Serotonin (5-HT) has been implicated in cerebral aneurysm rupture, but it is unclear whether 5-HT plays a role in aortic aneurysm development and rupture, despite well known contractile effects of 5-HT through aortic 5-HT receptors. Abdominal aortic aneurysms (AAAs) induced by angiotensin II (AngII) infusion to mice exhibit periaortic inflammation and are prone to rupture. Periaortic fat (PAF), a potential source of 5-HT through tryptophan hydroxylase 1 (Tph1), has been implicated in AAA development. We quantified mRNA abundance of 5-HT receptors (Htr1b, Htr2a, Htr2b, Htr3a, and Htr7) and Tph1 in thoracic and abdominal aortas and surrounding PAF. Compared with other 5-HT receptors, we detected high levels of serotonin 3 receptor type a (Htr3a) mRNA in the abdominal aortas and abdominal PAF. Tph1 mRNA and 5-HT immunostaining were detected in aortas and PAF, with 5-HT levels higher in abdominal than thoracic PAF, and higher in epididymal white than interscapular brown fat. AngII infusion facilitated evoked [3H]5-HT release from thoracic PAF and modestly reduced 5-HT levels in thoracic PAF and brown fat. Based on a high level of Htr3a mRNA in abdominal aortas and PAF, we investigated the development of AngII-induced AAAs when serotonin 3 receptors were pharmacologically antagonized with tropisetron. Tropisetron abrogated abdominal aortic lumen diameters, aneurysm (distal thoracic aneurysm and AAA) incidence, maximal AAA diameters, and aortic weights of AngII-infused male mice. These findings indicate a novel role for serotonin 3 receptor in AAA development, with a potential clinically relevant contribution for PAF as a local source of 5-HT. Significance Statement: Aortic aneurysms are life-threatening vascular disorders with no effective therapeutics. This study identified antagonism of the serotonin 3 receptor as a potential therapeutic target to reduce the formation and severity of experimentally-induced aneurysms in the thoracic and abdominal aorta. Additionally, periaortic fat was identified as a potential site for serotonin production in the development of aortic aneurysms.

AB - Serotonin (5-HT) has been implicated in cerebral aneurysm rupture, but it is unclear whether 5-HT plays a role in aortic aneurysm development and rupture, despite well known contractile effects of 5-HT through aortic 5-HT receptors. Abdominal aortic aneurysms (AAAs) induced by angiotensin II (AngII) infusion to mice exhibit periaortic inflammation and are prone to rupture. Periaortic fat (PAF), a potential source of 5-HT through tryptophan hydroxylase 1 (Tph1), has been implicated in AAA development. We quantified mRNA abundance of 5-HT receptors (Htr1b, Htr2a, Htr2b, Htr3a, and Htr7) and Tph1 in thoracic and abdominal aortas and surrounding PAF. Compared with other 5-HT receptors, we detected high levels of serotonin 3 receptor type a (Htr3a) mRNA in the abdominal aortas and abdominal PAF. Tph1 mRNA and 5-HT immunostaining were detected in aortas and PAF, with 5-HT levels higher in abdominal than thoracic PAF, and higher in epididymal white than interscapular brown fat. AngII infusion facilitated evoked [3H]5-HT release from thoracic PAF and modestly reduced 5-HT levels in thoracic PAF and brown fat. Based on a high level of Htr3a mRNA in abdominal aortas and PAF, we investigated the development of AngII-induced AAAs when serotonin 3 receptors were pharmacologically antagonized with tropisetron. Tropisetron abrogated abdominal aortic lumen diameters, aneurysm (distal thoracic aneurysm and AAA) incidence, maximal AAA diameters, and aortic weights of AngII-infused male mice. These findings indicate a novel role for serotonin 3 receptor in AAA development, with a potential clinically relevant contribution for PAF as a local source of 5-HT. Significance Statement: Aortic aneurysms are life-threatening vascular disorders with no effective therapeutics. This study identified antagonism of the serotonin 3 receptor as a potential therapeutic target to reduce the formation and severity of experimentally-induced aneurysms in the thoracic and abdominal aorta. Additionally, periaortic fat was identified as a potential site for serotonin production in the development of aortic aneurysms.

KW - Angiotensin

KW - Aortic aneurysm

KW - Periaortic fat

KW - Serotonin

KW - Serotonin 3 receptors

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C2 - 40023595

AN - SCOPUS:85217932419

SN - 0022-3565

VL - 392

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

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M1 - 100533

ER -

Serotonin 3 receptor antagonism reduces angiotensin II–induced abdominal aortic aneurysms: Contribution of periaortic fat–derived serotonin

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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