title: Pericytes as Inducers of Rapid, Matrix Metalloproteinase-9-Dependent Capillary Damage during Ischemia.
abstract: Blood-brain barrier disruption (BBB) and release of toxic blood molecules into the brain contributes to neuronal injury during stroke and other cerebrovascular diseases. While pericytes are builders and custodians of the BBB in the normal brain, their impact on BBB integrity during ischemia remains unclear. We imaged pericyte-labeled transgenic mice with in vivo two-photon microscopy to examine the relationship between pericytes and blood plasma leakage during photothrombotic occlusion of cortical capillaries. Upon cessation of capillary flow, we observed that plasma leakage occurred with three times greater frequency in regions where pericyte somata adjoined the endothelium. Pericyte somata covered only 7% of the total capillary length in cortex, indicating that a disproportionate amount of leakage occurred from a small fraction of the capillary bed. Plasma leakage was preceded by rapid activation of matrix metalloproteinase (MMP) at pericyte somata, which was visualized at high resolution in vivo using a fluorescent probe for matrix metalloproteinase-2/9 activity, fluorescein isothiocyanate (FITC)-gelatin. Coinjection of an MMP-9 inhibitor, but not an MMP-2 inhibitor, reduced pericyte-associated FITC-gelatin fluorescence and plasma leakage. These results suggest that pericytes contribute to rapid and localized proteolytic degradation of the BBB during cerebral ischemia.
  
  
  
  Pericytes are a key component of the neurovascular unit and are essential for normal BBB function. However, during acute ischemia, we find that pericytes are involved in creating rapid and heterogeneous BBB disruption in the capillary bed. The mechanism by which pericytes contribute to BBB damage warrants further investigation, as it may yield new therapeutic targets for acute stroke injury and other neurological diseases involving capillary flow impairment.
authors.affiliation: Department of Neurosciences and.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Underly
authors.affiliation: Department of Neurosciences and.
authors.forename: Manuel
authors.initials: M
authors.lastname: Levy
authors.affiliation: Department of Neurosciences and.
authors.forename: David A
authors.identifier: 0000-0003-0177-0069
authors.initials: DA
authors.lastname: Hartmann
authors.affiliation: Department of Neurosciences and.
authors.forename: Roger I
authors.initials: RI
authors.lastname: Grant
authors.affiliation: Department of Neurosciences and.
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Watson
authors.affiliation: Department of Neurosciences and shiha@musc.edu.|Center for Biomedical Imaging, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Andy Y
authors.initials: AY
authors.lastname: Shih
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology; D002545:Brain Ischemia / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D002196:Capillaries / Q000201:enzymology / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000503:physiopathology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020286:Pericytes / Q000201:enzymology / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D020521:Stroke / Q000201:enzymology / Q000503:physiopathology
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: blood–brain barrier; capillary; matrix-metalloproteinase; pericyte; stroke; two-photon imaging