title: In the hypoxic central nervous system, endothelial cell proliferation is followed by astrocyte activation, proliferation, and increased expression of the alpha 6 beta 4 integrin and dystroglycan.
abstract: Cerebral hypoxia induces a profound angiogenic response in the central nervous system (CNS). Using a mouse model of chronic cerebral hypoxia, we previously demonstrated that angiogenic vessels in the hypoxic CNS show marked upregulation of the extracellular matrix (ECM) protein fibronectin, along with increased expression of its major receptor, alpha 5 beta 1 integrin on brain endothelial cells (BEC). As cerebral hypoxia also leads to glial activation, the aim of the current study was to define the temporal relationship between BEC responses and glial cell activation in this model of cerebral hypoxia. This revealed that BEC fibronectin/alpha 5 beta 1 integrin expression and proliferation both reached maximal level after 4-day hypoxia. Interestingly, up to 4-day hypoxia, all dividing cells were BEC, but at later time-points proliferating astrocytes were also observed. GFAP staining revealed that hypoxia induced marked astrocyte activation that reached maximal level between 7- and 14-day hypoxia. As newly formed cerebral capillaries require ensheathment by astrocyte end-feet to acquire mature brain endothelium characteristics, we next examined how expression of astrocyte end-feet adhesion molecules is regulated by hypoxia. This showed that the astrocyte adhesion receptors alpha 6 beta 4 integrin and dystroglycan were both markedly upregulated, with a time-course that closely resembled astrocyte activation. Taken together, this evidence shows that cerebral hypoxia promotes first an endothelial response, in which fibronectin promotes BEC proliferation. This is then followed by an astrocyte response, involving astrocyte activation, proliferation, and reorganization of astrocyte end-feet, which correlates with increased expression of astrocyte end-feet adhesion molecules.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Longxuan
authors.initials: L
authors.lastname: Li
authors.forename: Jennifer V
authors.initials: JV
authors.lastname: Welser
authors.forename: Paula
authors.initials: P
authors.lastname: Dore-Duffy
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: del Zoppo
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Lamanna
authors.forename: Richard
authors.initials: R
authors.lastname: Milner
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001253:Astrocytes / Q000502:physiology*; D001921:Brain / Q000098:blood supply / Q000503:physiopathology; D002196:Capillaries / Q000503:physiopathology; D049109:Cell Proliferation; D002908:Chronic Disease; D062507:Claudin-5; D004195:Disease Models, Animal; D049030:Dystroglycans / Q000378:metabolism*; D042783:Endothelial Cells / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein; D002534:Hypoxia, Brain / Q000503:physiopathology*; D039161:Integrin alpha6beta4 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D013997:Time Factors; D062826:Zonula Occludens-1 Protein
chemical_list: D000954:Antigens, Surface; D062507:Claudin-5; C491511:Cldn5 protein, mouse; D005353:Fibronectins; D005904:Glial Fibrillary Acidic Protein; D039161:Integrin alpha6beta4; C095910:MECA-32 antigen, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; C528900:glial fibrillary astrocytic protein, mouse; D049030:Dystroglycans