AlSiraj Yasir, Ensor Charles M, English Victoria, Loria Analia, Ali Heba, Cassis Lisa A
Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky; Department of Pediatrics, University of Kentucky, Lexington, Kentucky.
Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky.
J Pharmacol Exp Ther. 2025 Feb;392(2):100533. doi: 10.1016/j.jpet.2024.100533. Epub 2024 Dec 24.
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 [H]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.
血清素（5-羟色胺，5-HT）与脑动脉瘤破裂有关，但尽管5-HT通过主动脉5-HT受体具有众所周知的收缩作用，其是否在主动脉瘤的发生和破裂中起作用尚不清楚。通过向小鼠输注血管紧张素II（AngII）诱导的腹主动脉瘤（AAA）表现出主动脉周围炎症且易于破裂。主动脉周围脂肪（PAF）是通过色氨酸羟化酶1（Tph1）产生5-HT的潜在来源，已被证明与AAA的发生有关。我们对胸主动脉和腹主动脉以及周围PAF中5-HT受体（Htr1b、Htr2a、Htr2b、Htr3a和Htr7）和Tph1的mRNA丰度进行了定量。与其他5-HT受体相比，我们在腹主动脉和腹部PAF中检测到高水平的血清素3 a型受体（Htr3a）mRNA。在主动脉和PAF中检测到Tph1 mRNA和5-HT免疫染色，腹部PAF中的5-HT水平高于胸部PAF，附睾白色脂肪中的水平高于肩胛间棕色脂肪。输注AngII促进了从胸部PAF诱发的[H]5-HT释放，并适度降低了胸部PAF和棕色脂肪中的5-HT水平。基于腹主动脉和PAF中高水平的Htr3a mRNA，我们研究了用托烷司琼对血清素3受体进行药理拮抗时AngII诱导的AAA的发展情况。托烷司琼消除了输注AngII的雄性小鼠的腹主动脉管腔直径、动脉瘤（胸段远端动脉瘤和AAA）发生率、最大AAA直径和主动脉重量。这些发现表明血清素3受体在AAA发展中具有新作用，PAF作为5-HT的局部来源可能具有临床相关作用。意义声明：主动脉瘤是危及生命的血管疾病，没有有效的治疗方法。本研究确定血清素3受体拮抗作用是减少实验诱导的胸主动脉和腹主动脉瘤形成和严重程度的潜在治疗靶点。此外，主动脉周围脂肪被确定为主动脉瘤发展过程中血清素产生的潜在部位。
