title: Ablation of astrocytic laminin impairs vascular smooth muscle cell function and leads to hemorrhagic stroke.
abstract: Astrocytes express laminin and assemble basement membranes (BMs) at their endfeet, which ensheath the cerebrovasculature. The function of astrocytic laminin in cerebrovascular integrity is unknown. We show that ablation of astrocytic laminin by tissue-specific Cre-mediated recombination disrupted endfeet BMs and led to hemorrhage in deep brain regions of adult mice, resembling human hypertensive hemorrhage. The lack of astrocytic laminin led to impaired function of vascular smooth muscle cells (VSMCs), where astrocytes have a closer association with VSMCs in small arterioles, and was associated with hemorrhagic vessels, which exhibited VSMC fragmentation and vascular wall disassembly. Acute disruption of astrocytic laminin in the striatum of adult mice also impaired VSMC function, indicating that laminin is necessary for VSMC maintenance. In vitro, both astrocytes and astrocytic laminin promoted brain VSMC differentiation. These results show that astrocytes regulate VSMCs and vascular integrity in small vessels of deep brain regions. Therefore, astrocytes may be a possible target for hemorrhagic stroke prevention and therapy.
authors.affiliation: Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Zu-Lin
authors.initials: ZL
authors.lastname: Chen
authors.forename: Yao
authors.initials: Y
authors.lastname: Yao
authors.forename: Erin H
authors.initials: EH
authors.lastname: Norris
authors.forename: Anna
authors.initials: A
authors.lastname: Kruyer
authors.forename: Odella
authors.initials: O
authors.lastname: Jno-Charles
authors.forename: Akbarshakh
authors.initials: A
authors.lastname: Akhmerov
authors.forename: Sidney
authors.initials: S
authors.lastname: Strickland
mesh_terms: D000818:Animals; D001160:Arterioles / Q000378:metabolism / Q000473:pathology; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D006624:Hippocampus / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D020299:Intracranial Hemorrhage, Hypertensive / Q000378:metabolism / Q000473:pathology*; D007797:Laminin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D012720:Severity of Illness Index
chemical_list: D007797:Laminin; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C089141:laminin gamma 1; D018995:Myosin Heavy Chains