5-Hydroxtryptamine Receptors in Systemic Hypertension: An Arterial Focus

Abstract

SUMMARYBackground: Serotonin (5-hydroxytryptamine [5-HT]) was named for its isolation from blood serum (sero-) and ability to contract smooth muscle (-tonin). Thus, its relationship with the cardiovascular system began with its discovery. Aims: This review will focus on the effects of 5-HT and its receptors in the vasculature, with a focus on their involvement in high blood pressure (hypertension). Two seemingly contradictory bodies of evidence exist that make it difficult to assign any one function to 5-HT in vascular control of blood pressure. Results: In vitro, 5-HT is an established vasoconstrictor, the effects of which are amplified in hypertension. By contrast, 5-HT (or its precursor 5-hydroxytryptophan) lowers blood pressure when given chronically in vivo. We will discuss ideas that might help us understand these differences, discuss relatively new pharmacology parameters (e.g. biased, inverse agonism) as they pertain to 5-HT receptors, and pose questions that are vital to answer so as to understand the role played by 5-HT in control of blood pressure, especially as it pertains to vascular function. Conclusions: Our goal is to understand if the actions of 5-HT in hypertension are physiologically and clinically relevant. The community understands 5-HT has complex cardiovascular effects, and clinical studies have proven equivocal in terms of the involvement of 5-HT. This article provides a balanced view of evidence/literature that illustrates involvement of 5-HT in hypertension as controversial. It contributes new pharmacological knowledge of 5-HT compounds, and poses timely questions as to how this field can move forward. The take home message is that the cardiovascular effects of 5-HT are markedly complex such that we have not yet answered the question of whether 5-HT is beneficial or detrimental to hypertension.

Serotonin passes through myoendothelial gap junctions to promote pulmonary arterial smooth muscle cell differentiation

“…Depending on the species and vessel of origin of the cells, and the concentration and duration of exposure to the monoamine, exogenous serotonin can exert a multitude of effects on vascular SMCs, including cell contraction, relaxation, migration, hypertrophy, and proliferation (1,12,17,38,61). These diverse responses are mediated by a variety of cell signaling pathways elicited by stimulation of various serotonin receptor subtypes and/or the internalization of the monoamine by its transporter.…”

Peroxisome Proliferator-Activated Receptor-γ Ameliorates Pulmonary Arterial Hypertension by Inhibiting 5-Hydroxytryptamine 2B Receptor

“…However, the pulmonary arteries exhibited the 2B receptor hyperresponsiveness in the course of PAH development, characterized by an increased expression of 5-HT2BR (Figure 2) and enhanced vasoreactivity to the 5-HT2BR agonist (Figures 3 and 4). Given that the 5-HT has a higher affinity for 5-HT2BR than 5-HT2AR, 45 the pathological importance of the increased 5-HT2BR is further underscored in the pathogenesis of PAH.…”

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

“…5‐HT also induced mitogenic response and was implicated in the remodeling of cardiovascular tissues, such as cardiac hypertrophy, fibrosis, valve hyperplasia,7 PAH, and hypertension 8. Circulating 5‐HT was elevated in patients with hypertension, PAH,9, 10 coronary and peripheral artery disease and was positively correlated with intima‐media thickness of the carotid arteries 11, 12, 13, 14, 15, 16. Plasma level of 5‐HT in coronary circulation was locally increased after angioplasty, and the release of 5‐HT was thought to be from the activated platelets 17, 18…”