Limits...
Endothelin-1 Mediates Brain Microvascular Dysfunction Leading to Long-Term Cognitive Impairment in a Model of Experimental Cerebral Malaria.

Freeman BD, Martins YC, Akide-Ndunge OB, Bruno FP, Wang H, Tanowitz HB, Spray DC, Desruisseaux MS - PLoS Pathog. (2016)

Bottom Line: Herein, we demonstrate that an endothelin type A receptor (ETA) antagonist prevented experimental cerebral malaria-induced neurocognitive impairments and improved survival.ETA antagonism prevented blood-brain barrier disruption and cerebral vasoconstriction during experimental cerebral malaria, and reduced brain endothelial activation, diminishing brain microvascular congestion.This vasoactive peptide may thus serve as a potential target for adjunctive therapy in the management of cerebral malaria.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America.

ABSTRACT
Plasmodium falciparum infection causes a wide spectrum of diseases, including cerebral malaria, a potentially life-threatening encephalopathy. Vasculopathy is thought to contribute to cerebral malaria pathogenesis. The vasoactive compound endothelin-1, a key participant in many inflammatory processes, likely mediates vascular and cognitive dysfunctions in cerebral malaria. We previously demonstrated that C57BL6 mice infected with P. berghei ANKA, our fatal experimental cerebral malaria model, sustained memory loss. Herein, we demonstrate that an endothelin type A receptor (ETA) antagonist prevented experimental cerebral malaria-induced neurocognitive impairments and improved survival. ETA antagonism prevented blood-brain barrier disruption and cerebral vasoconstriction during experimental cerebral malaria, and reduced brain endothelial activation, diminishing brain microvascular congestion. Furthermore, exogenous endothelin-1 administration to P. berghei NK65-infected mice, a model generally regarded as a non-cerebral malaria negative control for P. berghei ANKA infection, led to experimental cerebral malaria-like memory deficits. Our data indicate that endothelin-1 is critical in the development of cerebrovascular and cognitive impairments with experimental cerebral malaria. This vasoactive peptide may thus serve as a potential target for adjunctive therapy in the management of cerebral malaria.

Show MeSH

Related in: MedlinePlus

ET-1 contributes to cerebral vascular constriction during ECM.Intravital microscopy was performed to measure vasoconstriction in the cortical microvasculature. (A) Baseline vessel diameters; One-way ANOVA with Tukey's analysis. (B) Change from baseline in vessel diameters at 6dpi. Vessels are marked at baseline, and the diameter of each marked vessel is measured, then graphed as a percentage its own baseline diameter for each mouse. PbA-infected mice displayed marked decreases in vessel patency relative to uninfected control mice. Administration of HJP272 prevented ECM-induced vasoconstriction; One-way ANOVA with Tukey's post-hoc group comparisons. (C-H) Representative images of pial vessels in uninfected (C,D), infected (E,F), and infected HJP272 treated mice (G,H) at 0 and 6dpi, respectively. * = p < 0.05. n = 7/group.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4816336&req=5

ppat.1005477.g005: ET-1 contributes to cerebral vascular constriction during ECM.Intravital microscopy was performed to measure vasoconstriction in the cortical microvasculature. (A) Baseline vessel diameters; One-way ANOVA with Tukey's analysis. (B) Change from baseline in vessel diameters at 6dpi. Vessels are marked at baseline, and the diameter of each marked vessel is measured, then graphed as a percentage its own baseline diameter for each mouse. PbA-infected mice displayed marked decreases in vessel patency relative to uninfected control mice. Administration of HJP272 prevented ECM-induced vasoconstriction; One-way ANOVA with Tukey's post-hoc group comparisons. (C-H) Representative images of pial vessels in uninfected (C,D), infected (E,F), and infected HJP272 treated mice (G,H) at 0 and 6dpi, respectively. * = p < 0.05. n = 7/group.

Mentions: Vascular dysfunction including large vessel infarcts, cerebral edema, and impaired tissue perfusion in the retinal microvasculature are important components of CM pathogenesis [24–26]. The neurological impairments present in ECM are often associated with vascular complications including vasoconstriction, vascular collapse, and vascular congestion ultimately leading to disruption of the BBB [7, 27]. In order to determine the association between ET-1 induced microvascular disease and adverse cognitive outcomes during ECM, we assessed cerebral microvascular patency using intravital microscopy through a closed cranial window. As demonstrated in Fig 5A, mean baseline vessel diameters did not vary significantly between the different experimental groups (Fig 5; 46.5 ± 4 in control v. 51.9 ± 5.5 in PbA v. 46.7 ± 5.9 in PbA+HJP272; P = NS). In corroboration with previous studies [5, 28], mice with ECM had a significant reduction in pial arterial diameter at 6 dpi, while healthy uninfected animals maintained stable vessel diameters over the course of the experiment (Fig 5B–5F; 66.7 ± 5.1% of baseline in PbA vs. 109.7 ± 12.5% of baseline in control; P < 0.05). Treatment with the selective ETARB, HJP-272 prevented the ECM-induced narrowing of the cerebral microvasculature (Fig 5B and 5E–5H; 105.5 ±12.6% of baseline in HJP-272 vs. 66.7 ± 5.1% in PbA; P < 0.05).


Endothelin-1 Mediates Brain Microvascular Dysfunction Leading to Long-Term Cognitive Impairment in a Model of Experimental Cerebral Malaria.

Freeman BD, Martins YC, Akide-Ndunge OB, Bruno FP, Wang H, Tanowitz HB, Spray DC, Desruisseaux MS - PLoS Pathog. (2016)

ET-1 contributes to cerebral vascular constriction during ECM.Intravital microscopy was performed to measure vasoconstriction in the cortical microvasculature. (A) Baseline vessel diameters; One-way ANOVA with Tukey's analysis. (B) Change from baseline in vessel diameters at 6dpi. Vessels are marked at baseline, and the diameter of each marked vessel is measured, then graphed as a percentage its own baseline diameter for each mouse. PbA-infected mice displayed marked decreases in vessel patency relative to uninfected control mice. Administration of HJP272 prevented ECM-induced vasoconstriction; One-way ANOVA with Tukey's post-hoc group comparisons. (C-H) Representative images of pial vessels in uninfected (C,D), infected (E,F), and infected HJP272 treated mice (G,H) at 0 and 6dpi, respectively. * = p < 0.05. n = 7/group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4816336&req=5

ppat.1005477.g005: ET-1 contributes to cerebral vascular constriction during ECM.Intravital microscopy was performed to measure vasoconstriction in the cortical microvasculature. (A) Baseline vessel diameters; One-way ANOVA with Tukey's analysis. (B) Change from baseline in vessel diameters at 6dpi. Vessels are marked at baseline, and the diameter of each marked vessel is measured, then graphed as a percentage its own baseline diameter for each mouse. PbA-infected mice displayed marked decreases in vessel patency relative to uninfected control mice. Administration of HJP272 prevented ECM-induced vasoconstriction; One-way ANOVA with Tukey's post-hoc group comparisons. (C-H) Representative images of pial vessels in uninfected (C,D), infected (E,F), and infected HJP272 treated mice (G,H) at 0 and 6dpi, respectively. * = p < 0.05. n = 7/group.
Mentions: Vascular dysfunction including large vessel infarcts, cerebral edema, and impaired tissue perfusion in the retinal microvasculature are important components of CM pathogenesis [24–26]. The neurological impairments present in ECM are often associated with vascular complications including vasoconstriction, vascular collapse, and vascular congestion ultimately leading to disruption of the BBB [7, 27]. In order to determine the association between ET-1 induced microvascular disease and adverse cognitive outcomes during ECM, we assessed cerebral microvascular patency using intravital microscopy through a closed cranial window. As demonstrated in Fig 5A, mean baseline vessel diameters did not vary significantly between the different experimental groups (Fig 5; 46.5 ± 4 in control v. 51.9 ± 5.5 in PbA v. 46.7 ± 5.9 in PbA+HJP272; P = NS). In corroboration with previous studies [5, 28], mice with ECM had a significant reduction in pial arterial diameter at 6 dpi, while healthy uninfected animals maintained stable vessel diameters over the course of the experiment (Fig 5B–5F; 66.7 ± 5.1% of baseline in PbA vs. 109.7 ± 12.5% of baseline in control; P < 0.05). Treatment with the selective ETARB, HJP-272 prevented the ECM-induced narrowing of the cerebral microvasculature (Fig 5B and 5E–5H; 105.5 ±12.6% of baseline in HJP-272 vs. 66.7 ± 5.1% in PbA; P < 0.05).

Bottom Line: Herein, we demonstrate that an endothelin type A receptor (ETA) antagonist prevented experimental cerebral malaria-induced neurocognitive impairments and improved survival.ETA antagonism prevented blood-brain barrier disruption and cerebral vasoconstriction during experimental cerebral malaria, and reduced brain endothelial activation, diminishing brain microvascular congestion.This vasoactive peptide may thus serve as a potential target for adjunctive therapy in the management of cerebral malaria.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America.

ABSTRACT
Plasmodium falciparum infection causes a wide spectrum of diseases, including cerebral malaria, a potentially life-threatening encephalopathy. Vasculopathy is thought to contribute to cerebral malaria pathogenesis. The vasoactive compound endothelin-1, a key participant in many inflammatory processes, likely mediates vascular and cognitive dysfunctions in cerebral malaria. We previously demonstrated that C57BL6 mice infected with P. berghei ANKA, our fatal experimental cerebral malaria model, sustained memory loss. Herein, we demonstrate that an endothelin type A receptor (ETA) antagonist prevented experimental cerebral malaria-induced neurocognitive impairments and improved survival. ETA antagonism prevented blood-brain barrier disruption and cerebral vasoconstriction during experimental cerebral malaria, and reduced brain endothelial activation, diminishing brain microvascular congestion. Furthermore, exogenous endothelin-1 administration to P. berghei NK65-infected mice, a model generally regarded as a non-cerebral malaria negative control for P. berghei ANKA infection, led to experimental cerebral malaria-like memory deficits. Our data indicate that endothelin-1 is critical in the development of cerebrovascular and cognitive impairments with experimental cerebral malaria. This vasoactive peptide may thus serve as a potential target for adjunctive therapy in the management of cerebral malaria.

Show MeSH
Related in: MedlinePlus