title: Early inhibition of MMP activity in ischemic rat brain promotes expression of tight junction proteins and angiogenesis during recovery.
abstract: In cerebral ischemia, matrix metalloproteinases (MMPs) have a dual role by acutely disrupting tight junction proteins (TJPs) in the blood-brain barrier (BBB) and chronically promoting angiogenesis. Since TJP remodeling of the neurovascular unit (NVU) is important in recovery and early inhibition of MMPs is neuroprotective, we hypothesized that short-term MMP inhibition would reduce infarct size and promote angiogenesis after ischemia. Adult spontaneously hypertensive rats had a transient middle cerebral artery occlusion with reperfusion. At the onset of ischemia, they received a single dose of the MMP inhibitor, GM6001. They were studied at multiple times up to 4 weeks with immunohistochemistry, biochemistry, and magnetic resonance imaging (MRI). We observed newly formed vessels in peri-infarct regions at 3 weeks after reperfusion. Dynamic contrast-enhanced MRI showed BBB opening in new vessels. Along with the new vessels, pericytes expressed zonula occludens-1 (ZO-1) and MMP-3, astrocytes expressed ZO-1, occludin, and MMP-2, while endothelial cells expressed claudin-5. The GM6001, which reduced tissue loss at 3 to 4 weeks, significantly increased new vessel formation with expression of TJPs and MMPs. Our results show that pericytes and astrocytes act spatiotemporally, contributing to extraendothelial TJP formation, and that MMPs are involved in BBB restoration during recovery. Early MMP inhibition benefits neurovascular remodeling after stroke.
authors.affiliation: Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Thompson
authors.forename: Saeid
authors.initials: S
authors.lastname: Taheri
authors.forename: Victor M
authors.initials: VM
authors.lastname: Salayandia
authors.forename: Thera A
authors.initials: TA
authors.lastname: McAvoy
authors.forename: Jeff W
authors.initials: JW
authors.lastname: Hill
authors.forename: Yirong
authors.initials: Y
authors.lastname: Yang
authors.forename: Eduardo Y
authors.initials: EY
authors.lastname: Estrada
authors.forename: Gary A
authors.initials: GA
authors.lastname: Rosenberg
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000196:embryology / Q000503:physiopathology; D015153:Blotting, Western; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004151:Dipeptides / Q000008:administration & dosage / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling; D008279:Magnetic Resonance Imaging; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051381:Rats; D011918:Rats, Inbred SHR; D062725:Tight Junction Proteins / Q000096:biosynthesis*
chemical_list: D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D062725:Tight Junction Proteins; D020782:Matrix Metalloproteinases