Relationship between serotonin and vascular dysfunction and the impact of 5-HT receptor blockade by sarpogrelate on vascular function in diabetes mellitus.

Diabetes mellitus affects the functions of large and small vessels, leading to complications broadly classified as macro-vascular complications, including peripheral arterial disease, heart disease, and stroke, and microvascular complications, including neuropathy, retinopathy, and nephropathy. Moreover, vascular dysfunction, including abnormal reactivity to endogenous substances, is often observed in patients with diabetes mellitus. Among various vasoactive substances, serotonin (5-hydroxytryptamine; 5-HT), which was first isolated from peripheral blood >70 years ago, plays a pivotal role in the vascular system. However, the role of 5-HT-mediated vascular function, including vasoconstriction, in diabetes mellitus-associated vascular complications remains unclear. In addition to the abnormal 5-HT responsiveness observed in patients with diabetes mellitus, 5-HT also contributes to diabetes-associated vasculopathy through its role in vascular wall remodeling. In this review, we first summarize the altered responses and downstream signaling pathways induced by 5-HT in large and small vessels in animal models of diabetes mellitus and in patients based on evidence from the past 30 years. We also discuss the effects of sarpogrelate, a 5-HT receptor antagonist, on vascular function in diabetes mellitus and highlight the importance of blocking vascular 5-HT receptors as an approach to mitigate diabetes-associated vascular dysfunction. Our overarching aim is to emphasize the importance of controlling 5-HT-mediated signaling in the vasculature to prevent and treat diabetes-associated vascular complications.