De-Compartmentalization of Plasma Serotonin Induces Changes in Vascular Reactivity: Possible Mechanism of Vascular Dysfunction in Experimental Cerebral Malaria

Introduction: Mice with experimental cerebral malaria (ECM) exhibit reduced nitric oxide (NO) bioavailability, loss of vascular integrity, and impaired cerebral microcirculatory blood flow in vivo, but ex vivo, cerebral arteries behave normally. We hypothesized that plasma factors explain the discrepancy between in vivo and ex vivo arterial vasoreactivity in ECM. Methods: Wire myography was used to assess reactivity of aortic rings to plasma from healthy or ECM mice. L-NAME, nifedipine, EGTA, and ketanserin were used to assess NO synthase (NOS), calcium, and serotonin effects, respectively. To compare luminal against abluminal stimulation, mesenteric arteries were cannulated and exposed to 3% plasma or 1 μM serotonin on the luminal and then abluminal sides of the vessels. Results (mean ± SD) were expressed as force (g) differences from baseline for wire myography (n = 4-6) and as changes in diameter from baseline (% or μm) for pressure myography (n = 2-5). Linear regression was used to quantify dose-response relationships; repeated measures one-way ANOVA was used to assess changes before and after exposures. Results: Healthy and ECM plasma induced dose-dependent increases in aortic ring tension: m = 0.12 ± 0.07 g/M, p < 0.0001, and m = 0.08 ± 0.04 g/M, p < 0.0001, respectively; the effect of healthy or ECM plasma was similar (p = 0.17). L-NAME increased tension by 0.52 ± 0.24 g (p = 0.003) in arteries exposed to healthy plasma and by 0.58 ± 0.32 g in those exposed to ECM plasma (p = 0.008). Nifedipine decreased tension to 0.08 ± 0.07 g (p = 0.0007) and 0.13 ± 0.16 g (p = 0.002) respectively; EGTA further decreased tension to baseline (-0.003 ± 0.06 g, p = 0.0001, and 0.04 ± 0.02 g, p = 0.0003). In rings pre-treated with L-NAME, ketanserin decreased tension by 60 ± 6 % in rings stimulated with healthy plasma (p = 0.0007), and by 57 ± 7 % in rings stimulated with ECM plasma (p = 0.006).Serotonin elicited a greater vasoconstrictive response when applied to the abluminal vs luminal surfaces of cannulated arteries (-43 ± 27 vs -5.2 ± 7 µm, p = 0.01), an effect that was recapitulated by 3% plasma (-45 ± 6 vs -0.7 ± 8 µm, p = 0.2). Conclusion: Serotonin is the primary factor in plasma responsible for constriction of aortic rings. This vasoconstriction is calcium-dependent and partially counterbalanced by NOS. Studies of intact arteries revealed plasma serotonin must reach the abluminal surface to induce vasoconstriction. Thus, loss of vascular integrity, accompanied by extravasation of plasma into smooth muscle, may contribute to vascular dysfunction in cerebral malaria. Funded by CNPq, CAPES, IOC-Fiocruz, NIAID 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.