Inhibition of 5‐hydroxytryptamine2A receptor prevents occlusive thrombus formation on neointima of the rabbit femoral artery

Abstract

Summary. Background: Thrombus propagation on disrupted plaque is a major cause of acute coronary events and serious complication after coronary intervention. 5-hydroxytryptamine (5-HT) is a potent vasoactive and platelet-aggregating substance that is predominantly mediated by 5-HT 2A receptor. However, the roles of 5-HT 2A receptor in occlusive thrombus formation on disrupted plaque remain obscure. Objective: We investigated the role of 5-HT 2A receptor in thrombus formation using a rabbit model of repeated balloon-injury. Methods: Three weeks after a first balloon-injury of the femoral arteries, luminal diameter, neointimal growth, and vasoconstriction by 5-HT in vitro were examined. Thrombus propagation and the role of 5-HT 2A receptor after a second balloon-injury were evaluated using sarpogrelate, a selective 5-HT 2A receptor antagonist. Results: Three weeks after the first balloon-injury, luminal stenosis was evident in the femoral arteries, where the neointima expressed tissue factor and 5-HT 2A receptor. The hypercontractile response of the stenotic arteries to 5-HT was significantly reduced by sarpogrelate. Balloon-injury of the neointima with substantially reduced blood flow promoted the formation of occlusive thrombus that was immunoreactive against glycoprotein IIb-IIIa, 5-HT 2A receptor and fibrin. Intravenous injection of sarpogrelate significantly inhibited ex vivo platelet aggregation induced by adenosine 5¢-diphosphate, thrombin and collagen alone as well as with 5-HT, and significantly prevented occlusive thrombus formation in vivo. Conclusions: The 5-HT 2A receptor appears to play a crucial role in occlusive thrombus formation in diseased arteries via platelet aggregation and vasoconstriction. Inhibition of 5-HT 2A receptor might help reduce the onset of acute coronary events and of acute coronary occlusion after the intervention.

Interactions between integrin αIIbβ3 and the serotonin transporter regulate serotonin transport and platelet aggregation in mice and humans

“…Chronic use of 5-HT selective reuptake inhibitors (SSRIs) decreases platelet 5-HT content and can exacerbate bleeding (3,4). Secreted 5-HT, acting on platelet 5-HT 2a receptors, has been proposed to augment the effects of other prothrombotic agents that act through integral membrane receptor proteins, including the αIIbβ3 complex (also known as glycoprotein GPIIb/IIIa) (5). These actions of 5-HT may also represent a pathway for platelet hyperactivity and spontaneous aggregation that is observed in patients with atherosclerotic disease (6).…”

Inhibition of 5‐Hydroxytryptamine Receptor 2B Reduced Vascular Restenosis and Mitigated the β‐Arrestin2–Mammalian Target of Rapamycin/p70S6K Pathway

“…In a porcine model, sarpogrelate inhibited 5‐HT–induced coronary contraction and spam 54, 55. Sarpogrelate ameliorated the progression of atherosclerosis, reduced intimal hyperplasia in vein graft, and inhibited thrombus formation on neointima in rabbit models 56, 57, 58. These pathological effects of sarpogrelate are thought to be mediated through 5‐HT2AR, whereas it also binds to 5‐HT2BR 59.…”

Effects of the 5-HT2A Antagonist Sarpogrelate on Walking Ability in Patients with Intermittent Claudication as Measured Using the Walking Impairment Questionnaire

“…It is stored in circulating platelets, and once platelets are activated at sites of endothelial injury, serotonin is released to play an important role in thrombotic occlusion. 16) In atherothrombotic disease such as PAD, plasma serotonin concentrations are increased substantially. 17) To date, 14 distinct subtypes of serotonin receptors have been identified by molecular techniques.…”