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KRIT1 Depletion Modifies Endothelial Cell Behavior Through Increased VEGF Signaling
Author(s) -
DiStefano Peter,
Kuebel Julia,
Sarelius Ingrid,
Glading Angela
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.418.4
Subject(s) - microbiology and biotechnology , endothelial stem cell , vascular permeability , endothelium , signal transduction , angiogenesis , chemistry , biology , immunology , cancer research , endocrinology , in vitro , biochemistry
Disruption of endothelial cell‐cell contact is a key event in many cardiovascular diseases, and a characteristic of pathologically activated vascular endothelium. The CCM family of proteins (KRIT1, 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 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 not the primary cause of disrupted endothelial cell‐cell contacts in the absence of KRIT1. Sources of Funding: AHA 14PRE20380009 to Peter DiStefano NIH HL117885‐01 to Angela Glading