Nitric oxide (NO) is a widespread gaseous messenger molecule that plays a role in multiple physiological processes including neuronal communication and cell survival. NO is synthesized from oxygen and the amino acid L-arginine by various nitric oxide synthase (NOS) enzymes, such as neuronal NOS and inducible NOS. NO is highly reactive, diffuses freely across membranes and has a half-life of just a few seconds. NO, generated and released by several types of immune effector cells, is toxic to many pathogens. In terms of its vasoactivity, NO, released from endothelial cells, relaxes vascular smooth muscle and this results in vasodilation. Some of the vasodilators previously discussed, e.g. bradykinin and histamine exert their effects, at least in part, by stimulating the formation of NO.
Using heterologous anti-NOS antiserum, NOS immunoreactivity has been detected in S
. Neuronal NOS-like immunoreactivity is found in the main nerve cords, the peripheral nervous system and putative sensory neurons32
. Presumably in these locations, any NO generated is involved in signaling cascades that are part of normal, internal parasite physiology. However, anti-inducible NOS antibodies label a variety of predominantly non-neuronal tissues, in parts of the gastrointestinal tract and with intense labeling at or near the surface of the worm32
. It has been suggested that NO-related pathways derived from these sources may play a role in parasite–host interactions, perhaps by permitting the parasites to respond not only to endogenous NO but also to host-derived NO. Indeed it has been demonstrated that exposure of adult schistosomes to an NO donor in vitro
does induce rapid changes in gene expression, though these changes are not large-scale34
. Some NO upregulated genes, such as cyclic nucleotide phosphodiesterase and calcineurin, and some down regulated genes, such as Rac GTPase, share similarity with genes that have previously been reported to be involved in NO signaling in other systems34
. The roles of other NO upregulated genes, (e.g. encoding a metal ion transport associated protein and a subunit of the coatomer complex), and some down regulated genes, (e.g. encoding a subunit of vacuolar ATP synthase, a putative coated vesicle membrane protein, and a putative ligand gated ion channel) are entirely unknown. Several other genes, both up and down regulated, encode hypothetical proteins with no homologs outside of the schistosomes34
Using a fluorescent indicator to directly detect NO in living adult S. mansoni
males revealed patchy staining in “epithelial-like cells” at least some of which are likely to be sensory35
. Whether NO is ever released by the parasites to act e.g. as a vasodilator is unknown. A complication is that worms secrete the heme-containing metabolite hemozoin as a waste product of hemoglobin digestion36
and it is known that heme products can inactivate NO37–39
. It is noteworthy that infection with the vascular nematode parasite Dirofilaria immitis
can lead to an alteration in the relaxation behavior of endothelial cells of the pulmonary artery, and NO has been implicated in this effect40
It seems likely that schistosomes would act as obstacles in blood vessels and this should lead to severe disturbances of blood flow including increased blood velocity past the endothelium. This is a known stimulus for NO release by endothelial cells41
. Acting as a vasodilator, such NO release would help restore blood flow levels and make it less imperative for the parasites to interfere directly in the process. In this view, schistosomes, rather than directly impinging on host vascular biochemistry in the many ways outlined in this review, act as simple parasites and rely completely on the host to maintain vascular homeostasis.