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Critical role of sphingosine-1-phosphate receptor-2 in the disruption of cerebrovascular integrity in experimental stroke.

Kim GS, Yang L, Zhang G, Zhao H, Selim M, McCullough LD, Kluk MJ, Sanchez T - Nat Commun (2015)

Bottom Line: In addition, inhibition of S1PR2 results in decreased matrix metalloproteinase (MMP)-9 activity in vivo and lower gelatinase activity in cerebral microvessels.S1PR2 immunopositivity is detected only in the ischemic microvessels of wild-type mice and in the cerebrovascular endothelium of human brain autopsy samples.In vitro, S1PR2 potently regulates the responses of the brain endothelium to ischaemic and inflammatory injury.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Emergency Medicine, the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Department of Surgery, the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.

ABSTRACT
The use and effectiveness of current stroke reperfusion therapies are limited by the complications of reperfusion injury, which include increased cerebrovascular permeability and haemorrhagic transformation. Sphingosine-1-phosphate (S1P) is emerging as a potent modulator of vascular integrity via its receptors (S1PR). By using genetic approaches and a S1PR2 antagonist (JTE013), here we show that S1PR2 plays a critical role in the induction of cerebrovascular permeability, development of intracerebral haemorrhage and neurovascular injury in experimental stroke. In addition, inhibition of S1PR2 results in decreased matrix metalloproteinase (MMP)-9 activity in vivo and lower gelatinase activity in cerebral microvessels. S1PR2 immunopositivity is detected only in the ischemic microvessels of wild-type mice and in the cerebrovascular endothelium of human brain autopsy samples. In vitro, S1PR2 potently regulates the responses of the brain endothelium to ischaemic and inflammatory injury. Therapeutic targeting of this novel pathway could have important translational relevance to stroke patients.

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Immunohistochemical analysis of S1PR2 in human brainS1PR2 was detected in endothelial cells of pial vessels and microvessels in autopsy specimens. Representative images are shown. A) Case 1, B) Case 2, C) Case 3, D) Case 4, E) Case 5. Pictures were taken at 60x magnification. Scale bar 30μm.
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Figure 8: Immunohistochemical analysis of S1PR2 in human brainS1PR2 was detected in endothelial cells of pial vessels and microvessels in autopsy specimens. Representative images are shown. A) Case 1, B) Case 2, C) Case 3, D) Case 4, E) Case 5. Pictures were taken at 60x magnification. Scale bar 30μm.

Mentions: Given our in vivo and in vitro findings, in order to assess their potential pathophysiological relevance in humans, we performed immunohistochemical (IHC) analysis of S1PR2 in human brain autopsy samples. The specificity of the S1PR2 antibody was determined as we have previously described 36: S1PR2 immunohistochemistry showed membranous and cytoplasmic staining only in S1PR2-transfected 293T cells and not in S1PR1-transfected or pcDNA3.1-transfected cells (Supplementary Figure 6). IHC analysis of human brain samples revealed S1PR2 positivity in the cerebrovascular endothelium (Figure 8, representative pictures). We found heterogeneous S1PR2 expression in the endothelium of pial vessels and microvessels throughout the brain in the 5 brain samples analyzed. The limited clinical data available for these patients (summarized in Supplementary Table 1) revealed various hypoxic/ischemic states including stroke, respiratory failure or sickle cell vaso-occlusive crisis. These data indicate that S1PR2 can be detected in the human cerebrovascular endothelium.


Critical role of sphingosine-1-phosphate receptor-2 in the disruption of cerebrovascular integrity in experimental stroke.

Kim GS, Yang L, Zhang G, Zhao H, Selim M, McCullough LD, Kluk MJ, Sanchez T - Nat Commun (2015)

Immunohistochemical analysis of S1PR2 in human brainS1PR2 was detected in endothelial cells of pial vessels and microvessels in autopsy specimens. Representative images are shown. A) Case 1, B) Case 2, C) Case 3, D) Case 4, E) Case 5. Pictures were taken at 60x magnification. Scale bar 30μm.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4587559&req=5

Figure 8: Immunohistochemical analysis of S1PR2 in human brainS1PR2 was detected in endothelial cells of pial vessels and microvessels in autopsy specimens. Representative images are shown. A) Case 1, B) Case 2, C) Case 3, D) Case 4, E) Case 5. Pictures were taken at 60x magnification. Scale bar 30μm.
Mentions: Given our in vivo and in vitro findings, in order to assess their potential pathophysiological relevance in humans, we performed immunohistochemical (IHC) analysis of S1PR2 in human brain autopsy samples. The specificity of the S1PR2 antibody was determined as we have previously described 36: S1PR2 immunohistochemistry showed membranous and cytoplasmic staining only in S1PR2-transfected 293T cells and not in S1PR1-transfected or pcDNA3.1-transfected cells (Supplementary Figure 6). IHC analysis of human brain samples revealed S1PR2 positivity in the cerebrovascular endothelium (Figure 8, representative pictures). We found heterogeneous S1PR2 expression in the endothelium of pial vessels and microvessels throughout the brain in the 5 brain samples analyzed. The limited clinical data available for these patients (summarized in Supplementary Table 1) revealed various hypoxic/ischemic states including stroke, respiratory failure or sickle cell vaso-occlusive crisis. These data indicate that S1PR2 can be detected in the human cerebrovascular endothelium.

Bottom Line: In addition, inhibition of S1PR2 results in decreased matrix metalloproteinase (MMP)-9 activity in vivo and lower gelatinase activity in cerebral microvessels.S1PR2 immunopositivity is detected only in the ischemic microvessels of wild-type mice and in the cerebrovascular endothelium of human brain autopsy samples.In vitro, S1PR2 potently regulates the responses of the brain endothelium to ischaemic and inflammatory injury.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Emergency Medicine, the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Department of Surgery, the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.

ABSTRACT
The use and effectiveness of current stroke reperfusion therapies are limited by the complications of reperfusion injury, which include increased cerebrovascular permeability and haemorrhagic transformation. Sphingosine-1-phosphate (S1P) is emerging as a potent modulator of vascular integrity via its receptors (S1PR). By using genetic approaches and a S1PR2 antagonist (JTE013), here we show that S1PR2 plays a critical role in the induction of cerebrovascular permeability, development of intracerebral haemorrhage and neurovascular injury in experimental stroke. In addition, inhibition of S1PR2 results in decreased matrix metalloproteinase (MMP)-9 activity in vivo and lower gelatinase activity in cerebral microvessels. S1PR2 immunopositivity is detected only in the ischemic microvessels of wild-type mice and in the cerebrovascular endothelium of human brain autopsy samples. In vitro, S1PR2 potently regulates the responses of the brain endothelium to ischaemic and inflammatory injury. Therapeutic targeting of this novel pathway could have important translational relevance to stroke patients.

Show MeSH
Related in: MedlinePlus