Abluminal plasma induces vasoconstriction meditated by serotonin and counterbalanced by endothelial nitric oxide synthase in healthy and malarial mouse arteries

Background & Purpose: Experimental cerebral malaria (ECM) is associated with abnormalities in cerebral perfusion, yet the mechanisms underlying vascular dysfunction remain incompletely defined. Experimental Approach: Ex vivo pressure myography of middle cerebral arteries (MCAs) was used to assess intrinsic arterial function in control and ECM mice. Mesenteric arteries were used to compare intraluminal perfusion versus abluminal superfusion with healthy plasma or serotonin (5-HT). Wire myography of aortic rings as a biosensor for plasma-derived vasoactive factors was used to investigate circulating modulators of vascular tone. Key Results: MCAs from ECM animals showed preserved constriction to 5-HT, preserved endothelium-dependent relaxation to methacholine (MCh), and intact responses to nitroprusside. MCh relaxation was inhibited by L-NAME, indicating preserved endothelial NO signaling. In aortic rings, ECM plasma produced concentration-dependent vasoconstriction, enhanced by NOS inhibition. Blockade of 5-HT₂A receptors with ketanserin abolished >80% of this constriction in a sex-independent manner, demonstrating that plasma 5-HT is the predominant circulating vasoconstrictor. Plasma or 5-HT induced robust vasoconstriction when applied abluminally, but not intraluminally. Conclusion & Implications: ECM does not cause intrinsic endothelial or smooth muscle dysfunction of the MCA. Vasoconstrictive responses to plasma from ECM or control mice were similar, suggesting no major differences in plasma vasoregulatory molecules. Plasma serotonin exerts a vasoconstrictive effect in the setting of NOS inhibition when plasma contacts the adventitial, but not the luminal, aspect of an artery. Based on these findings, we propose that normal circulating levels of serotonin could potentially have vasoconstrictive effects in disease conditions that compromise vascular barrier integrity.