title: HIF-dependent regulation of AKAP12 (gravin) in the control of human vascular endothelial function.
abstract: Hypoxia has been widely implicated in many pathological conditions, including those associated with inflammation and tumorigenesis. A number of recent studies have implicated hypoxia in the control of vasculogenesis and permeability, the basis for which is not fully understood. Here we examine the transcriptional regulation of angiogenesis and permeability by hypoxia in endothelial cells. Guided by a global profiling approach in cultured endothelial cells, these studies revealed the selective induction of human gravin (protein kinase A anchoring protein 12) by hypoxia. Analysis of the cloned gravin promoter identified a functional hypoxia-responsive region including 2 binding sites for hypoxia-inducible factor (HIF). Site-directed mutagenesis identified the most distal HIF-binding site as essential for the induction of gravin by hypoxia. Further studies examining gravin gain and loss of function confirmed strong dependence of gravin in control of microvascular endothelial tube formation, wherein gravin functions as a "braking" system for angiogenesis. Additional studies in confluent endothelia revealed that gravin functionally couples to control endothelial barrier function in response to protein kinase A (PKA) agonists. Taken together, these results demonstrate transcriptional coordination of gravin by HIF-1α and amplified PKA-dependent endothelial responses. These findings provide an important link between hypoxia and metabolic conditions associated with inflammation and angiogenesis.
authors.affiliation: 1Mucosal Inflammation Program, University of Colorado, 12700 E. 19th Ave, Aurora, CO 80045, USA. sean.colgan@ucdenver.edu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Weissmüller
authors.forename: Louise E
authors.initials: LE
authors.lastname: Glover
authors.forename: Blair
authors.initials: B
authors.lastname: Fennimore
authors.forename: Valerie F
authors.initials: VF
authors.lastname: Curtis
authors.forename: Christopher F
authors.initials: CF
authors.lastname: MacManus
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Ehrentraut
authors.forename: Eric L
authors.initials: EL
authors.lastname: Campbell
authors.forename: Melanie
authors.initials: M
authors.lastname: Scully
authors.forename: Bryon D
authors.initials: BD
authors.lastname: Grove
authors.forename: Sean P
authors.initials: SP
authors.lastname: Colgan
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D016297:Mutagenesis, Site-Directed
chemical_list: D054758:A Kinase Anchor Proteins; C491162:AKAP12 protein, human; D018797:Cell Cycle Proteins; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: angiogenesis; barrier function; hypoxia-inducible factor; permeability
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