PMID- 33192578 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20201117 IS - 1664-042X (Print) IS - 1664-042X (Electronic) IS - 1664-042X (Linking) VI - 11 DP - 2020 TI - Increased Immunosignals of Collagen IV and Fibronectin Indicate Ischemic Consequences for the Neurovascular Matrix Adhesion Zone in Various Animal Models and Human Stroke Tissue. PG - 575598 LID - 10.3389/fphys.2020.575598 [doi] LID - 575598 AB - Ischemic stroke causes cellular alterations in the "neurovascular unit" (NVU) comprising neurons, glia, and the vasculature, and affects the blood-brain barrier (BBB) with adjacent extracellular matrix (ECM). Limited data are available for the zone between the NVU and ECM that has not yet considered for neuroprotective approaches. This study describes ischemia-induced alterations for two main components of the neurovascular matrix adhesion zone (NMZ), i.e., collagen IV as basement membrane constituent and fibronectin as crucial part of the ECM, in conjunction with traditional NVU elements. For spatio-temporal characterization of these structures, multiple immunofluorescence labeling was applied to tissues affected by focal cerebral ischemia using a filament-based model in mice (4, 24, and 72 h of ischemia), a thromboembolic model in rats (24 h of ischemia), a coagulation-based model in sheep (2 weeks of ischemia), and human autoptic stroke tissue (3 weeks of ischemia). An increased fibronectin immunofluorescence signal demarcated ischemia-affected areas in mice, along with an increased collagen IV signal and BBB impairment indicated by serum albumin extravasation. Quantifications revealed a region-specific pattern with highest collagen IV and fibronectin intensities in most severely affected neocortical areas, followed by a gradual decline toward the border zone and non-affected regions. Comparing 4 and 24 h of ischemia, the subcortical fibronectin signal increased significantly over time, whereas neocortical areas displayed only a gradual increase. Qualitative analyses confirmed increased fibronectin and collagen IV signals in ischemic areas from all tissues and time points investigated. While the increased collagen IV signal was restricted to vessels, fibronectin appeared diffusely arranged in the parenchyma with focal accumulations associated to the vasculature. Integrin alpha(5) appeared enriched in the vicinity of fibronectin and vascular elements, while most of the non-vascular NVU elements showed complementary staining patterns referring to fibronectin. This spatio-temporal characterization of ischemia-related alterations of collagen IV and fibronectin in various stroke models and human autoptic tissue shows that ischemic consequences are not limited to traditional NVU components and the ECM, but also involve the NMZ. Future research should explore more components and the pathophysiological properties of the NMZ as a possible target for novel neuroprotective approaches. CI - Copyright (c) 2020 Michalski, Spielvogel, Puchta, Reimann, Barthel, Nitzsche, Mages, Jager, Martens, Horn, Schob and Hartig. FAU - Michalski, Dominik AU - Michalski D AD - Department of Neurology, University of Leipzig, Leipzig, Germany. FAU - Spielvogel, Emma AU - Spielvogel E AD - Department of Neurology, University of Leipzig, Leipzig, Germany. AD - Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany. FAU - Puchta, Joana AU - Puchta J AD - Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany. AD - Department of Neuroradiology, University of Leipzig, Leipzig, Germany. FAU - Reimann, Willi AU - Reimann W AD - Department of Neurology, University of Leipzig, Leipzig, Germany. AD - Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany. FAU - Barthel, Henryk AU - Barthel H AD - Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany. FAU - Nitzsche, Bjorn AU - Nitzsche B AD - Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany. AD - Institute of Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, Germany. FAU - Mages, Bianca AU - Mages B AD - Institute of Anatomy, University of Leipzig, Leipzig, Germany. FAU - Jager, Carsten AU - Jager C AD - Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany. FAU - Martens, Henrik AU - Martens H AD - Synaptic Systems GmbH, Gottingen, Germany. FAU - Horn, Anja K E AU - Horn AKE AD - Institute of Anatomy and Cell Biology I and German Center for Vertigo and Balance Disorders, Ludwig-Maximilians-University, Munich, Germany. FAU - Schob, Stefan AU - Schob S AD - Department of Neuroradiology, University of Leipzig, Leipzig, Germany. FAU - Hartig, Wolfgang AU - Hartig W AD - Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany. LA - eng PT - Journal Article DEP - 20201026 PL - Switzerland TA - Front Physiol JT - Frontiers in physiology JID - 101549006 PMC - PMC7649770 OTO - NOTNLM OT - basement membrane OT - blood-brain barrier OT - collagen IV OT - extracellular matrix OT - fibronectin OT - stroke EDAT- 2020/11/17 06:00 MHDA- 2020/11/17 06:01 PMCR- 2020/10/26 CRDT- 2020/11/16 08:44 PHST- 2020/06/23 00:00 [received] PHST- 2020/09/23 00:00 [accepted] PHST- 2020/11/16 08:44 [entrez] PHST- 2020/11/17 06:00 [pubmed] PHST- 2020/11/17 06:01 [medline] PHST- 2020/10/26 00:00 [pmc-release] AID - 10.3389/fphys.2020.575598 [doi] PST - epublish SO - Front Physiol. 2020 Oct 26;11:575598. doi: 10.3389/fphys.2020.575598. eCollection 2020.