Abstract 17283: Upregulation of Serotonin 5HT2A and 5HT2B Receptors Contributes to Increased Vascular Contractions in Type 2 Diabetes
Serotonin (5HT), a neurohumoral factor released from activated platelets, acts on smooth muscle and endothelial cells to regulate vascular reactivity. Although 5HT1B and 5HT2B receptors are expressed in mouse aorta, 5HT-induced contractions of normal arteries are primarily mediated by activation of 5HT2A receptors on smooth muscle. We hypothesized that increased contractions to 5HT in arteries from diabetics are mediated by upregulation of multiple 5HT receptor subtypes. To test this hypothesis, we compared responses of isolated aortic rings to various 5HT agonists and receptor expression (5HT1B, 5HT2A and 5HT2B) in aorta from non-diabetic (C57BLKS/J, ND, n=3–7 per agonist) compared to leptin receptor deficient Type 2 diabetic mice (BKS.Cg-Dock7m +/+ Leprdb/J, DB, n=3–8 per agonist). Maximal contractions (mg tension) at 10 uM for each agonist dose response curve are presented (mean ± SEM, * p<0.05 vs ND). 5HT produced dose dependent contractions of ND aorta in contrast to selective 5HT2A agonists (α-methyl-5HT and BRL54443), 5HT2B agonists (BW723C86 and norfenfluramine), or the 5HT1B agonist (CP93129). Removal of endothelium increased contractions to 5HT (505 ± 91 mg, p<0.05) but had no effect on contractions to 5HT1B or 5HT2B agonists. Contractions to 5HT, 5HT2A agonists (α-methyl-5HT and BRL54443), and 5HT2B agonists (BW723C86 and norfenfluramine) were all markedly increased in DB aorta. Contractions to the 5HT1B agonist (CP93129) were similar in NB and DB aorta. Similar to the changes in vascular responses, protein expression of both 5HT2A and 5HT2B receptors was increased in DB compared to ND aorta. We conclude that the enhanced contraction to 5HT of arteries from diabetics is due, in part, to upregulation of both 5HT2A and 5HT2B receptors in vascular smooth muscle but not 5HT1B receptors. Alterations in downstream signaling pathways activated by 5HT binding to 5HT2A and 5HT2B receptors may be increased in diabetes, contributing to abnormal vasoconstriction.
- © 2010 by American Heart Association, Inc.