title: Defining the critical hypoxic threshold that promotes vascular remodeling in the brain.
abstract: In animal models, hypoxic pre-conditioning confers protection against subsequent neurological insults, mediated in part through an extensive vascular remodeling response. In light of the therapeutic potential of this effect, the goal of this study was to establish the dose-response relationship between level of hypoxia and the extent of cerebrovascular modeling, and to define the mildest level of hypoxia that promotes remodeling. Mice were exposed to different levels of continuous hypoxia (8-21% O2) for seven days before several aspects of vascular remodeling were evaluated, including endothelial proliferation, total vascular area, arteriogenesis, and fibronectin/α5β1 integrin expression. For most events, the threshold level of hypoxia that stimulated remodeling was 12-13% O2. Interestingly, many parameters displayed a biphasic dose-response curve, with peak levels attained at 10% O2, but declined thereafter. Further analysis in the 12-13% O2 range revealed that vascular remodeling occurs by two separate mechanisms: (i) endothelial hyperplasia, triggered by a hypoxic threshold of 13% O2, which leads to increased capillary growth, and (ii) endothelial hypertrophy, triggered by a more severe hypoxic threshold of 12% O2, which leads to expansion of large vessels and arteriogenesis. Taken together, these results define the hypoxic thresholds for vascular remodeling in the brain, and point to two separate mechanisms mediating this process.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Amin
authors.initials: A
authors.lastname: Boroujerdi
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: rmilner@scripps.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: Milner
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply*; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000502:physiology; D002534:Hypoxia, Brain / Q000503:physiopathology*; D007150:Immunohistochemistry; D019194:Ischemic Preconditioning / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000502:physiology*; D066253:Vascular Remodeling / Q000502:physiology*
keywords: Angiogenesis; Arteriogenesis; Blood–brain barrier (BBB); Dose–response; Endothelial cells; Fibronectin; Hypoxic threshold; Vascular remodeling; α5 integrin