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Targeted over-expression of endothelin-1 in astrocytes leads to more severe brain damage and vasospasm after subarachnoid hemorrhage.

Yeung PK, Shen J, Chung SS, Chung SK - BMC Neurosci (2013)

Bottom Line: The present study suggests that astrocytic ET-1 involves in SAH-induced cerebral injury, edema and vasospasm, through ETA receptor and PKC-mediated potassium channel dysfunction.Administration of ABT-627 (ETA receptor antagonist) and SR 49059 (vasopressin V1a receptor antagonist) resulted in amelioration of edema and vasospasm in mice following SAH.These data provide a strong rationale to investigate SR 49059 and ABT-627 as therapeutic drugs for the treatment of SAH patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. skchung@hkucc.hku.hk.

ABSTRACT

Background: Endothelin-1 (ET-1) is a potent vasoconstrictor, and astrocytic ET-1 is reported to play a role in the pathogenesis of cerebral ischemic injury and cytotoxic edema. However, it is still unknown whether astrocytic ET-1 also contributes to vasogenic edema and vasospasm during subarachnoid hemorrhage (SAH). In the present study, transgenic mice with astrocytic endothelin-1 over-expression (GET-1 mice) were used to investigate the pathophysiological role of ET-1 in SAH pathogenesis.

Results: The GET-1 mice experienced a higher mortality rate and significantly more severe neurological deficits, blood-brain barrier breakdown and vasogenic edema compared to the non-transgenic (Ntg) mice following SAH. Oral administration of vasopressin V1a receptor antagonist, SR 49059, significantly reduced the cerebral water content in the GET-1 mice. Furthermore, the GET-1 mice showed significantly more pronounced middle cerebral arterial (MCA) constriction after SAH. Immunocytochemical analysis showed that the calcium-activated potassium channels and the phospho-eNOS were significantly downregulated, whereas PKC-α expression was significantly upregulated in the MCA of the GET-1 mice when compared to Ntg mice after SAH. Administration of ABT-627 (ETA receptor antagonist) significantly down-regulated PKC-α expression in the MCA of the GET-1 mice following SAH.

Conclusions: The present study suggests that astrocytic ET-1 involves in SAH-induced cerebral injury, edema and vasospasm, through ETA receptor and PKC-mediated potassium channel dysfunction. Administration of ABT-627 (ETA receptor antagonist) and SR 49059 (vasopressin V1a receptor antagonist) resulted in amelioration of edema and vasospasm in mice following SAH. These data provide a strong rationale to investigate SR 49059 and ABT-627 as therapeutic drugs for the treatment of SAH patients.

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Vasospasm analysis and NOS expressions in MCA after subarachnoid hemorrhage. (A) Representative pictures show the histological analysis of MCA. Vasospasm is observed in both Ntg and GET-1 brain after SAH when compared to that of their sham group (n = 5). Histogram shows the arterial diameter measurement of MCA in Ntg and GET-1 after SAH. (*P < 0.05, Mann-Whitey test; n = 5 for Ntg and GET-1 mice). Expression of NOS in MCA after SAH. Representative photos shows the (B) nNOS, (C) eNOS and (D)p-eNOS expressions of sham and SAH of MCA in Ntg and GET-1 brain. Arrowheads show the expression of nNOS (tunica adventitia) and eNOS/p-eNOS (tunica intima), (n = 4 for each group of mice). Histograms show the quantification results (relative value in percentage) of immunocytochemistry of sham and SAH of Ntg and GET-1 MCA sections. (*P < 0.05, **P < 0.01, ANOVA followed by Bonferroni’s test; n = 4 for each group of mice).
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Figure 3: Vasospasm analysis and NOS expressions in MCA after subarachnoid hemorrhage. (A) Representative pictures show the histological analysis of MCA. Vasospasm is observed in both Ntg and GET-1 brain after SAH when compared to that of their sham group (n = 5). Histogram shows the arterial diameter measurement of MCA in Ntg and GET-1 after SAH. (*P < 0.05, Mann-Whitey test; n = 5 for Ntg and GET-1 mice). Expression of NOS in MCA after SAH. Representative photos shows the (B) nNOS, (C) eNOS and (D)p-eNOS expressions of sham and SAH of MCA in Ntg and GET-1 brain. Arrowheads show the expression of nNOS (tunica adventitia) and eNOS/p-eNOS (tunica intima), (n = 4 for each group of mice). Histograms show the quantification results (relative value in percentage) of immunocytochemistry of sham and SAH of Ntg and GET-1 MCA sections. (*P < 0.05, **P < 0.01, ANOVA followed by Bonferroni’s test; n = 4 for each group of mice).

Mentions: To investigate the role of astrocytic ET-1 on SAH-induced vasospasm, MCAs were isolated and examined from both genotypes after SAH. Vasospasm in the MCA was observed in both Ntg and GET-1 when compared to their sham groups, and the MCA in the brains of the GET-1 mice showed more severe constrictions compared to the Ntg mice (Sham: Ntg 126.2 ± 7.4 μm vs GET-1 132.2 ± 10.4 μm; SAH: Ntg 106.5 ± 2.3 μm vs GET-1 99.7 ± 3.1 μm, n = 5, *P < 0.05 by Mann–Whitney test) (Figure 3A).


Targeted over-expression of endothelin-1 in astrocytes leads to more severe brain damage and vasospasm after subarachnoid hemorrhage.

Yeung PK, Shen J, Chung SS, Chung SK - BMC Neurosci (2013)

Vasospasm analysis and NOS expressions in MCA after subarachnoid hemorrhage. (A) Representative pictures show the histological analysis of MCA. Vasospasm is observed in both Ntg and GET-1 brain after SAH when compared to that of their sham group (n = 5). Histogram shows the arterial diameter measurement of MCA in Ntg and GET-1 after SAH. (*P < 0.05, Mann-Whitey test; n = 5 for Ntg and GET-1 mice). Expression of NOS in MCA after SAH. Representative photos shows the (B) nNOS, (C) eNOS and (D)p-eNOS expressions of sham and SAH of MCA in Ntg and GET-1 brain. Arrowheads show the expression of nNOS (tunica adventitia) and eNOS/p-eNOS (tunica intima), (n = 4 for each group of mice). Histograms show the quantification results (relative value in percentage) of immunocytochemistry of sham and SAH of Ntg and GET-1 MCA sections. (*P < 0.05, **P < 0.01, ANOVA followed by Bonferroni’s test; n = 4 for each group of mice).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3815232&req=5

Figure 3: Vasospasm analysis and NOS expressions in MCA after subarachnoid hemorrhage. (A) Representative pictures show the histological analysis of MCA. Vasospasm is observed in both Ntg and GET-1 brain after SAH when compared to that of their sham group (n = 5). Histogram shows the arterial diameter measurement of MCA in Ntg and GET-1 after SAH. (*P < 0.05, Mann-Whitey test; n = 5 for Ntg and GET-1 mice). Expression of NOS in MCA after SAH. Representative photos shows the (B) nNOS, (C) eNOS and (D)p-eNOS expressions of sham and SAH of MCA in Ntg and GET-1 brain. Arrowheads show the expression of nNOS (tunica adventitia) and eNOS/p-eNOS (tunica intima), (n = 4 for each group of mice). Histograms show the quantification results (relative value in percentage) of immunocytochemistry of sham and SAH of Ntg and GET-1 MCA sections. (*P < 0.05, **P < 0.01, ANOVA followed by Bonferroni’s test; n = 4 for each group of mice).
Mentions: To investigate the role of astrocytic ET-1 on SAH-induced vasospasm, MCAs were isolated and examined from both genotypes after SAH. Vasospasm in the MCA was observed in both Ntg and GET-1 when compared to their sham groups, and the MCA in the brains of the GET-1 mice showed more severe constrictions compared to the Ntg mice (Sham: Ntg 126.2 ± 7.4 μm vs GET-1 132.2 ± 10.4 μm; SAH: Ntg 106.5 ± 2.3 μm vs GET-1 99.7 ± 3.1 μm, n = 5, *P < 0.05 by Mann–Whitney test) (Figure 3A).

Bottom Line: The present study suggests that astrocytic ET-1 involves in SAH-induced cerebral injury, edema and vasospasm, through ETA receptor and PKC-mediated potassium channel dysfunction.Administration of ABT-627 (ETA receptor antagonist) and SR 49059 (vasopressin V1a receptor antagonist) resulted in amelioration of edema and vasospasm in mice following SAH.These data provide a strong rationale to investigate SR 49059 and ABT-627 as therapeutic drugs for the treatment of SAH patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. skchung@hkucc.hku.hk.

ABSTRACT

Background: Endothelin-1 (ET-1) is a potent vasoconstrictor, and astrocytic ET-1 is reported to play a role in the pathogenesis of cerebral ischemic injury and cytotoxic edema. However, it is still unknown whether astrocytic ET-1 also contributes to vasogenic edema and vasospasm during subarachnoid hemorrhage (SAH). In the present study, transgenic mice with astrocytic endothelin-1 over-expression (GET-1 mice) were used to investigate the pathophysiological role of ET-1 in SAH pathogenesis.

Results: The GET-1 mice experienced a higher mortality rate and significantly more severe neurological deficits, blood-brain barrier breakdown and vasogenic edema compared to the non-transgenic (Ntg) mice following SAH. Oral administration of vasopressin V1a receptor antagonist, SR 49059, significantly reduced the cerebral water content in the GET-1 mice. Furthermore, the GET-1 mice showed significantly more pronounced middle cerebral arterial (MCA) constriction after SAH. Immunocytochemical analysis showed that the calcium-activated potassium channels and the phospho-eNOS were significantly downregulated, whereas PKC-α expression was significantly upregulated in the MCA of the GET-1 mice when compared to Ntg mice after SAH. Administration of ABT-627 (ETA receptor antagonist) significantly down-regulated PKC-α expression in the MCA of the GET-1 mice following SAH.

Conclusions: The present study suggests that astrocytic ET-1 involves in SAH-induced cerebral injury, edema and vasospasm, through ETA receptor and PKC-mediated potassium channel dysfunction. Administration of ABT-627 (ETA receptor antagonist) and SR 49059 (vasopressin V1a receptor antagonist) resulted in amelioration of edema and vasospasm in mice following SAH. These data provide a strong rationale to investigate SR 49059 and ABT-627 as therapeutic drugs for the treatment of SAH patients.

Show MeSH
Related in: MedlinePlus