title: Role of serotonin in angiogenesis: induction of angiogenesis by sarpogrelate via endothelial 5-HT1B/Akt/eNOS pathway in diabetic mice.
abstract: Serotonin (5-hydroxytryptamine, 5-HT) plays a crucial role in peripheral artery disease (PAD) and diabetes mellitus (DM). In these conditions, the balance between the 5-HT2A receptor in smooth muscle cells and the 5-HT1B receptor in endothelial cells (ECs) regulates vascular tonus. In the present study, we focused on the role of 5-HT in endothelial dysfunction using a selective 5-HT2A receptor blocker, sarpogrelate. In human EC, 5-HT markedly stimulated eNOS expression and the phosphorylation of eNOS, Akt and ERK1/2. In addition, a dose-dependent increase in tubule-formation on Matrigel was observed after 5-HT treatment. In contrast, high glucose significantly inhibited tubule formation and eNOS expression through inactivation of Akt, while 5-HT significantly attenuated these actions of high glucose (P<0.01). These results indicate that 5-HT stimulated angiogenesis through activation of Akt in ECs. However, in clinical situations, 5-HT seems to act as the "devil". To examine the role of 5-HT in diabetic PAD, a hindlimb ischemia model was created in diabetic mice. The blood flow ratio of the ischemic to non-ischemic limb was significantly lower in DM mice than in normal mice, while sarpogrelate significantly attenuated the decrease in the blood flow ratio compared to control (P<0.01). Consistently, the decrease in eNOS expression and Akt activity in DM mice was significantly attenuated by sarpogrelate. Overall, the present study demonstrated that selective inhibition of 5-HT2A by sarpogrelate significantly restored ischemic limb blood perfusion in a severe diabetic mouse model through stimulation of the eNOS/Akt pathway via the endothelial 5-HT1B receptor. Enhancement of vasodilation and angiogenesis by sarpogrelate might provide a unique treatment for PAD and DM patients.
authors.affiliation: Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Iwabayashi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Taniyama
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sanada
authors.forename: Junya
authors.initials: J
authors.lastname: Azuma
authors.forename: Kazuma
authors.initials: K
authors.lastname: Iekushi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kusunoki
authors.forename: Amarnath
authors.initials: A
authors.lastname: Chatterjee
authors.forename: Keita
authors.initials: K
authors.lastname: Okayama
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D006614:Hindlimb; D006801:Humans; D007511:Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D044302:Receptor, Serotonin, 5-HT1B / Q000187:drug effects* / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013386:Succinates / Q000494:pharmacology*; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects
chemical_list: D043925:Angiogenesis Inducing Agents; C470302:HTR1B protein, human; D044302:Receptor, Serotonin, 5-HT1B; D044402:Receptor, Serotonin, 5-HT2A; D012702:Serotonin Antagonists; D013386:Succinates; C064294:sarpogrelate; D012701:Serotonin; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt