Serotonin-Induced Vasoconstriction Mediated by NAD+ as a Therapy for Bleeding Disorders

Objectives: Vasoconstriction mediated by endothelial and platelet-derived serotonin is a crucial mechanism altering local flow resistance and promoting platelet aggregation. Thus, localized vasoconstriction may offer a novel strategy for life-threatening bleeding in cardiovascular surgery and interventions. NAD+ plays a significant role in serotonin metabolism; however, its role in hemostasis remains unknown.

Methods: We used a tail-bleeding mouse model on wild-type, WASP−/− thrombocytopenic, and hemophilia-A mice previously subjected to chemotherapy. Further analyses were performed using FACS, qPCR and ELISA. Local vasoconstriction was assessed by ultrasound.

Result: We showed, that NAD+ increased platelet number and activation in WT and WASP−/− mice. Furthermore, NAD+ promotes hemostasis by dramatically reducing the hemorrhagic volume and bleeding-time in WT mice. Although chemotherapy reduced circulating platelet counts in both NAD+ and PBS-treated mice, the NAD+-treated group displayed reduced bleeding with no mortality. Furthermore, NAD+ was tested following common platelet aggregation inhibitors (aspirin and clopidogrel). NAD+ was able to restore hemostasis in WT mice subjected to platelet inactivation and in hemophilia-A mice, while mice in the control-group died from excessive bleeding. Moreover, NAD+ did not alter the expression of coagulation factors nor change the PT/PTT but was associated with an increased systemic level of serotonin. Mechanistically, we show that NAD+ treatment promoted vasoconstriction at the site of injury and administration of serotonin receptor antagonists, or an inhibitor of tryptophan hydroxylase-1, a synthase that catalyzes the conversion of tryptophan to serotonin, reversed NAD+-mediated hemostasis.

Conclusion: Overall, our findings identify NAD+ as a novel potential candidate to optimize hemostasis in for the treatment of uncontrollable bleeding situations.

Publication History

Article published online:
19 February 2021