Abstract 11468: Role of Serotonin in Angiogenesis: Induction of Angiogenesis by Sarpogrelate via Endothelial 5-HT1B/Akt/eNOS Pathway in Diabetic Mice
Background: Serotonin (5-hydroxytryptamine, 5-HT) plays a crucial role in pathophysiological conditions of 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 (EC) 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.
Methods and Results: (in vitro) Stimulating Human Aortic Endothelial Cells (HAECs) with 5-HT (10μ M) upregulates eNOS expression and phosphorylation of eNOS, Akt and ERK1/2. In addition, a dose-dependent increase in tubule -formation was observed on Matrigel after 5-HT treatment (P<0.01). 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. (in vivo) To examine the role of 5-HT in diabetic PAD, a hindlimb ischemia model was created and sarpogrelate (50mg/kg/day) was administered to streptozotocin (200mg/kg) induced severe diabetic mice. Sarpogrelate administration did not alter the streptozotocin induced body weight loss and increased blood glucose level. 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 (P<0.01).
Conclusion: 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.
- © 2011 by American Heart Association, Inc.