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- INI - Artigos de Periódicos [3460]
- IOC - Artigos de Periódicos [12642]
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NITRIC OXIDE SYNTHASE DYSFUNCTION CONTRIBUTES TO IMPAIRED CEREBROARTERIOLAR REACTIVITY IN EXPERIMENTAL CEREBRAL MALARIA
Nitric Oxide Synthase Dysfunction
Cerebrovascular dysfunction
Plasmodium berghei
Autor(es)
Afiliação
Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA.
Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA.
Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA.
Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA.
Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA.
University of California. Department of Bioengineering. San Diego, CA, USA.
Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA / Fundação Oswaldo Cruz. Instituto de pesquisa Clínica Evandro Chagas. Serviço de Parasitologia. Rio de Janeiro, RJ, Brasil.
Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA.
Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre Malária. Rio de Janeiro, RJ, Brasil.
Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA.
Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA.
Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA.
Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA.
University of California. Department of Bioengineering. San Diego, CA, USA.
Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA / Fundação Oswaldo Cruz. Instituto de pesquisa Clínica Evandro Chagas. Serviço de Parasitologia. Rio de Janeiro, RJ, Brasil.
Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA.
Center for Malaria Research. La Jolla Bioengineering Institute. San Diego, CA, USA / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa sobre Malária. Rio de Janeiro, RJ, Brasil.
Resumo em Inglês
Cerebrovascular dysfunction plays a key role in the pathogenesis of cerebral malaria. In experimental cerebral malaria (ECM)
induced by Plasmodium berghei ANKA, cerebrovascular dysfunction characterized by vascular constriction, occlusion and
damage results in impaired perfusion and reduced cerebral blood flow and oxygenation, and has been linked to low nitric
oxide (NO) bioavailability. Here, we directly assessed cerebrovascular function in ECM using a novel cranial window method
for intravital microscopy of the pial microcirculation and probed the role of NOS isoforms and phosphorylation patterns in
the impaired vascular responses. We show that pial arteriolar responses to endothelial NOS (eNOS) and neuronal NOS
(nNOS) agonists (Acetylcholine (ACh) and N-Methyl-D-Aspartate (NMDA)) were blunted in mice with ECM, and could be
partially recovered by exogenous supplementation of tetrahydrobiopterin (BH4). Pial arterioles in non-ECM mice infected by
Plasmodium berghei NK65 remained relatively responsive to the agonists and were not significantly affected by BH4
treatment. These findings, together with the observed blunting of NO production upon stimulation by the agonists,
decrease in total NOS activity, augmentation of lipid peroxidation levels, upregulation of eNOS protein expression, and
increase in eNOS and nNOS monomerization in the brain during ECM development strongly indicate a state of eNOS/nNOS
uncoupling likely mediated by oxidative stress. Furthermore, the downregulation of Serine 1176 (S1176) phosphorylation of
eNOS, which correlated with a decrease in cerebrovascular wall shear stress, implicates hemorheological disturbances in
eNOS dysfunction in ECM. Finally, pial arterioles responded to superfusion with the NO donor, S-Nitroso-L-glutathione
(GSNO), but with decreased intensity, indicating that not only NO production but also signaling is perturbed during ECM.
Therefore, the pathological impairment of eNOS and nNOS functions contribute importantly to cerebrovascular dysfunction
in ECM and the recovery of intrinsic functionality of NOS to increase NO bioavailability and restore vascular health
represents a target for ECM treatment.
Palavras-chave em inglês
Cerebral MalariaNitric Oxide Synthase Dysfunction
Cerebrovascular dysfunction
Plasmodium berghei
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