title: Progranulin deficiency promotes post-ischemic blood-brain barrier disruption.
abstract: Loss-of-function mutations of progranulin (PGRN) have been linked to frontotemporal dementia, but little is known about the effects of PGRN deficiency on the brain in health and disease. PGRN has been implicated in neurovascular development, inflammation, and Wnt signaling, a pathway involved in the formation of the blood-brain barrier (BBB). Because BBB alterations and inflammation contribute to ischemic brain injury, we examined the role of PGRN in the brain damage produced by ischemia-reperfusion. PGRN(+/-) and PGRN(-/-) mice underwent middle cerebral artery occlusion (MCAO) with monitoring of cerebral blood flow. Infarct volume and motor deficits were assessed 72 h later. Post-ischemic inflammation was examined by expression of inflammatory genes and flow cytometry. BBB structure and permeability were examined by electron microscopy (EM) and Evans blue (EB) extravasation, respectively. MCAO resulted in ~60% larger infarcts in PGRN(+/-) and PGRN(-/-) mice, an effect independent of hemodynamic factors or post-ischemic inflammation. Rather, massive hemorrhages and post-ischemic BBB disruption were observed, unrelated to degradation of tight junction (TJ) proteins or matrix metalloproteinases (MMPs). By EM, TJ were 30-52% shorter, fewer, and less interlocking, suggesting a weaker seal between endothelial cells. Intracerebral injection of platelet-derived growth factor-CC (PDGF-CC), which increases BBB permeability, resulted in a more severe BBB breakdown in PGRN(+/-) and PGRN(-/-) than wild-type mice. We describe a previously unrecognized involvement of PGRN in the expression of key ultrastructural features of the BBB. Such a novel vasoprotective role of PGRN may contribute to brain dysfunction and damage in conditions associated with reduced PGRN function.
authors: Brain and Mind Research Institute, Departments of Radiology and Microbiology and Immunology, Weill Cornell Medical College, New York, New York 10021.
authors: Katherine
authors: K
authors: Jackman
authors: Timo
authors: T
authors: Kahles
authors: Diane
authors: D
authors: Lane
authors: Lidia
authors: L
authors: Garcia-Bonilla
authors: Takato
authors: T
authors: Abe
authors: Carmen
authors: C
authors: Capone
authors: Karin
authors: K
authors: Hochrainer
authors: Henning
authors: H
authors: Voss
authors: Ping
authors: P
authors: Zhou
authors: Aihao
authors: A
authors: Ding
authors: Josef
authors: J
authors: Anrather
authors: Costantino
authors: C
authors: Iadecola
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000503:physiopathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology; D042783:Endothelial Cells / Q000378:metabolism; D000077155:Granulins; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000077153:Progranulins; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology; D020521:Stroke / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D020782:Matrix Metalloproteinases
keywords: blood–brain barrier; frontotemporal dementia; neurovascular unit; progranulin; stroke