Endothelial endothelin-1 over-expression using receptor tyrosine kinase tie-1 promoter leads to more severe vascular permeability and blood brain barrier breakdown after transient middle cerebral artery occlusion.
Endothelin-1 (ET-1) is up-regulated in the endothelial cells and astrocytes under ischemia. Transgenic mice with astrocytic ET-1 over-expression (GET-1) showed more severe neurological deficit and larger infarct after transient middle cerebral artery occlusion (MCAO). Here, the significance of endothelial ET-1 in ischemic brain injury was investigated using transgenic mice with the endothelial ET-1 over-expression (TET-1). Increased ET-1 level was observed in the TET-1 brain infarct core after transient MCAO. ET(A) receptor expression was induced in the penumbra and ET(A) antagonist (A-147627) partially normalized the infarct volume and neurological deficit. In the infarct core of TET-1 brain, superoxide, nitrotyrosine, and gp91(phox) levels were increased. TET-1 brain displayed increased matrix metalloproteinase-2 expression, water content, immunoglobulin leakage and decreased occludin level in the ipsilateral hemisphere indicative of BBB breakdown and hemispheric edema. Interestingly, AQP-4 expression was increased in the penumbra of TET-1 brain following transient MCAO leading to the water accumulation. Taken together, endothelial ET-1 over-expression and ETA receptor activation contributes to the increased oxidative stress, water accumulation and BBB breakdown after transient MCAO leading to more severe neurological deficit and increased infarct.
Leung
Justin W C
JW
Department of Anatomy, The University of Hong Kong, HKSAR, China.
Chung
Stephen S M
SS
Chung
Sookja K
SK
D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D000077868:Atrasentan; D001812:Blood-Brain Barrier / Q000473:pathology* / Q000503:physiopathology; D001921:Brain / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D002199:Capillary Permeability; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D007136:Immunoglobulins / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology* / Q000503:physiopathology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D062793:Occludin; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D011759:Pyrrolidines / Q000008:administration & dosage; D044022:Receptor, Endothelin A / Q000378:metabolism; D042810:Receptor, TIE-1 / Q000235:genetics; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014867:Water / Q000378:metabolism
C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D062793:Occludin; C568986:Ocln protein, mouse; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D014867:Water; D013481:Superoxides; C002744:3-nitrotyrosine; D014443:Tyrosine; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D042810:Receptor, TIE-1; D020778:Matrix Metalloproteinase 2; D000077868:Atrasentan