Mechanisms of Carcinoid Syndrome: Serotonin-Induced Vasoconstrictor Impairment and Endothelial Dysfunction

Background: Patients with neuroendocrine tumors (NETs) who develop carcinoid syndrome have hemodynamic instability. During invasive procedures, severe hypotensive events are associated with elevated serum serotonin (5-HT) secreted by the tumors, but the specific vascular mechanisms and receptors that mediate this response remain unclear. We hypothesized that 5-HT impairs vasoconstrictor responsiveness and mice with NET metastases exhibit altered vasomotor function. Methods: Male and female J:Nu mice (~4 mo), were injected with 1x 10 ⁷ BON-1 NET cells to induce liver metastases (BON-1, n=17) or phosphate-buffered saline control (CON, n=17). After 10 weeks for tumor development, we harvested mesenteric arteries and assessed vascular function by pressure myography. We performed dose-response curves to vasodilators acetylcholine (ACh), 5-HT, 5-carboxamidotryptamine maleate (5-CT), and sodium nitroprusside (SNP), and vasoconstrictors arginine vasopressin (AVP) and endothelin-1 (ET-1). Responses were repeated following incubation with nitric oxide (NO) synthase inhibitor (L-NAME), 5-HT, or 5-HT _2A antagonist MDL 11,939. Maximal responses are presented as mean±SEM. Results: Incubation with 5-HT decreased vasoconstriction to AVP (51±4% vs 20±5%, p<0.0001), but not vasoconstriction to ET-1 (44±8% vs 47±10%, p=0.85). AVP or ET-1-mediated vasoconstriction were similar between groups (all p>0.05). Compared with CON, BON-1 mice had impaired vasodilation to ACh (CON:75±5% vs BON1: 57±7%, p=0.042) and 5-HT (60±5% vs 43±5%, p=0.02). The ACh response after LNAME incubation was similar between BON-1 and CON (all p>0.05), indicating reduced NO bioavailability in BON1 arteries. There was a trend for lower serotonin-mediated vasodilation with 5-HT _2A blockade in the CON (p=0.07), but not BON-1 (p=0.38), suggesting that lower 5-HT _2A activation impaired vasodilation in BON-1. Furthermore, 5-CT vasodilation was similar between groups (p=0.42), indicating that 5-HT ₁ and 5-HT ₇ signaling are maintained in BON-1 mice. Vasodilation to SNP was similar between groups (p=0.49), indicating no difference in smooth muscle cell responsiveness to NO. Discussion: We demonstrate that 5-HT inhibits vasoconstriction specifically to AVP. As NET metastases are associated with higher serum 5-HT, our results suggest that hemodynamic instability in patients with NETs may be attributed to impaired AVP-mediated mechanisms. Similar AVP-responsiveness between BON-1 and CON mice reflects that these studies were performed ex vivo in a tumor-free environment. The impaired vasodilation in the BON-1 mice is likely due to impaired endothelial cell function, which could attribute to increased cardiovascular risk. Targeting 5-HT or AVP signaling pathways could improve hemodynamic stability in patients with NET metastases.

Medical Research Foundation of Oregon

This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.