Altered vasomotor function and endothelial impairment in a neuroendocrine tumor mouse model.

Neuroendocrine tumors (NETs) secrete vasoactive hormones that promote hemodynamic instability. This study investigated whether NETs alter vascular responsiveness using a murine model. J:Nu mice received intrasplenic injections of BON-1 NET cells (BON-1, n = 21) or PBS (VEH, n = 21) and monitored for 10 weeks. Liver metastases were identified by histological analysis, chromogranin A expression, and presence of ALDH1-positive cancer stem cells. Vasomotor function of isolated mesenteric arteries was assessed to acetylcholine, serotonin, vasopressin, and endothelin-1, and with nitric oxide synthase inhibition (L-NAME), 5-HT receptor blockade, or serotonin incubation. BON-1 mice exhibited impaired vasodilation to acetylcholine and serotonin compared with VEH (p < 0.05), specifically in males (p < 0.001). L-NAME and 5-HT1b/d receptor blockade attenuated vasodilatory responses to serotonin only in VEH mice. Serotonin incubation reduced vasopressin-mediated vasoconstriction (p < 0.0001). These findings indicate that NET metastases are associated with impaired serotonin-mediated vasodilation, which is associated with reduced nitric oxide bioavailability, altered 5-HT1b/d receptor action, and sex-dependent impairment of endothelium-dependent vasodilation. Elevated serotonin levels may further compromise vasopressin-mediated vasoconstriction. The presence of NET metastases alters vascular responsiveness, which may contribute to hemodynamic instability.