Abstract
Although 5HT2A receptors mediate contractions of normal arteries to serotonin (5HT), in some cardiovascular diseases, other receptor subtypes contribute to the marked increase in serotonin contractions. We hypothesized that enhanced contractions of arteries from diabetics to 5HT are mediated by an increased contribution from multiple 5HT receptor subtypes. We compared responses to selective 5HT receptor agonists and expression of 5HT receptor isoforms (5HT1B, 5HT2A, and 5HT2B) in aorta from nondiabetic (ND) compared to type 2 diabetic mice (DB, BKS.Cg-Dock7 m+/+Leprdb/J). 5HT, 5HT2A (TCB2 and BRL54443), and 5HT2B (norfenfluramine and BW723C86) receptor agonists produced concentration-dependent contractions of ND arteries that were markedly increased in DB arteries. Neither ND nor DB arteries contracted to a 5HT1B receptor agonist. MDL11939, a 5HT2A receptor antagonist, and LY272015, a 5HT2B receptor antagonist, reduced contractions of arteries from DB to 5HT more than ND. Expression of 5HT1B, 5HT2A, and 5HT2B receptor subtypes was similar in ND and DB. Inhibition of rho kinase decreased contractions to 5HT and 5HT2A and 5HT2B receptor agonists in ND and DB. We conclude that in contrast to other cardiovascular diseases, enhanced contraction of arteries from diabetics to 5HT is not due to a change in expression of multiple 5HT receptor subtypes.
Highlights
Vascular responses to serotonin (5HT), a neurohumoral factor released from activated platelets implicated in vasospasm of large coronary and cerebral arteries, are determined by multiple factors including binding to distinct receptor subtypes, species, sex, and vessel size [1,2,3,4,5]
The present study demonstrates that the augmented contractions of arteries in a model of type 2 diabetes are primarily due to changes in signaling pathways within smooth muscle that regulate calcium sensitivity of contractile proteins rather than a change in endothelial-derived vasoactive factors or specific serotonin receptor subtypes
In both non-diabetic and diabetic mice, contractions to serotonin were mediated by activation of both 5HT2A and 5HT2B receptors
Summary
Vascular responses to serotonin (5HT), a neurohumoral factor released from activated platelets implicated in vasospasm of large coronary and cerebral arteries, are determined by multiple factors including binding to distinct receptor subtypes, species, sex, and vessel size [1,2,3,4,5]. Serotonin-induced contractions are mediated by 5HT2A receptors on vascular smooth muscle, which activates the rho/rho kinase pathway to regulate phosphorylation of myosin light chain phosphatase and myosin light chain [5, 6]. Activation of 5HT2A receptors predominates in normal arteries [4, 5], expression and function of other serotonergic receptor subtypes (primarily 5HT1B and 5HT2B) are upregulated in hypertension and atherosclerosis contributing to greater contractions to serotonin [7,8,9,10,11,12,13]. The increased contraction to serotonin may be mediated, in part, by reductions in nitric oxide bioavailability, this mechanism alone cannot account for the marked hypercontractile response observed in many
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