title: KRIT1 protein depletion modifies endothelial cell behavior via increased vascular endothelial growth factor (VEGF) signaling.
abstract: Disruption of endothelial cell-cell contact is a key event in many cardiovascular diseases and a characteristic of pathologically activated vascular endothelium. The CCM (cerebral cavernous malformation) family of proteins (KRIT1 (Krev-interaction trapped 1), PDCD10, and CCM2) are critical regulators of endothelial cell-cell contact and vascular homeostasis. Here we show novel regulation of vascular endothelial growth factor (VEGF) signaling in KRIT1-depleted endothelial cells. Loss of KRIT1 and PDCD10, but not CCM2, increases nuclear β-catenin signaling and up-regulates VEGF-A protein expression. In KRIT1-depleted cells, increased VEGF-A levels led to increased VEGF receptor 2 (VEGFR2) activation and subsequent alteration of cytoskeletal organization, migration, and barrier function and to in vivo endothelial permeability in KRIT1-deficient animals. VEGFR2 activation also increases β-catenin phosphorylation but is only partially responsible for KRIT1 depletion-dependent disruption of cell-cell contacts. Thus, VEGF signaling contributes to modifying endothelial function in KRIT1-deficient cells and microvessel permeability in Krit1(+/-) mice; however, VEGF signaling is likely not the only contributor to disrupted endothelial cell-cell contacts in the absence of KRIT1.
authors.affiliation: From the Department of Pharmacology and Physiology, University of Rochester, Rochester, New York 14642.
authors.forename: Peter V
authors.initials: PV
authors.lastname: DiStefano
authors.affiliation: From the Department of Pharmacology and Physiology, University of Rochester, Rochester, New York 14642.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Kuebel
authors.affiliation: From the Department of Pharmacology and Physiology, University of Rochester, Rochester, New York 14642.
authors.forename: Ingrid H
authors.initials: IH
authors.lastname: Sarelius
authors.affiliation: From the Department of Pharmacology and Physiology, University of Rochester, Rochester, New York 14642 angela_glading@urmc.rochester.edu.
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Glading
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002199:Capillary Permeability; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002417:Cattle; D002450:Cell Communication; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D042783:Endothelial Cells / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D000075927:KRIT1 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C502544:CCM2 protein, human; D002352:Carrier Proteins; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C495390:PDCD10 protein, human; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Adherens Junction; CCM; Krit1; Permeability; Phosphotyrosine Signaling; Vascular Endothelial Growth Factor (VEGF); β-Catenin (B-Catenin)