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Fell‐Muir Lecture: Regulatory mechanisms of skeletal and connective tissue development and homeostasis – lessons from studies of human disorders
Author(s) -
Olsen Bjorn R.,
Berendsen Agnes D.,
Besschetnova Tatiana Y.,
Duan Xuchen,
Hu Kai
Publication year - 2016
Publication title -
international journal of experimental pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.671
H-Index - 72
eISSN - 1365-2613
pISSN - 0959-9673
DOI - 10.1111/iep.12198
Subject(s) - biology , vascular endothelial growth factor , nfat , vascular endothelial growth factor b , microbiology and biotechnology , endocrinology , cancer research , vascular endothelial growth factor a , medicine , transcription factor , genetics , gene , vegf receptors
Summary Studies of proliferative hemangiomas have led to the discovery that interactions of endothelial cells with extracellular matrix and/or Vascular Endothelial Growth Factor ( VEGF )‐A stimulate the expression of VEGFR 1, the VEGF decoy receptor, and suppress VEGF ‐dependent VEGFR 2 signalling by a mechanism that requires the matrix‐binding receptor Anthrax Toxin Receptor ( ANTXR )1, VEGFR 2, β1 integrin and the Nuclear Factor of Activated T cells (NFAT) . In hemangioma endothelial cells, all these components are present, but are functionally compromised, so that the levels of VEGFR 1 are extremely low and VEGFR 2 signalling is constitutively active. Consequently, the levels of Hypoxia Inducible Factor ( HIF )‐1α and its transcriptional targets, VEGF ‐A and C‐X‐C motif chemokine 12 (CxCl12), are elevated and a positive VEGF ‐A feedback loop is established. Overexpression of ANTXR 1, carrying a heterozygous Ala‐to‐Thr mutation, induces hemangioma‐like signalling in control endothelial cells; VEGF signalling is normalized when wild‐type ANTXR 1 is overexpressed in hemangioma cells. These findings suggest that ANTXR 1 functions as a negative regulator of VEGF ‐A signalling. Studies of a mouse model of the Growth Retardation, Alopecia, Pseudo‐anodontia and Optic Atrophy ( GAPO ) syndrome, caused by the loss‐of‐function mutations in ANTXR 1, as well as knock‐in mice carrying the Ala‐to‐Thr ANTXR 1 mutation, confirm that ANTXR 1 functions as a suppressor of VEGF ‐A signalling. Cutaneous endothelial cells isolated from ANTXR 1‐deficient mice exhibit low levels of VEGFR 1, elevated levels of VEGF ‐A, HIF ‐1α and CxCl12 and activated VEGFR 2 signalling as in hemangioma. Increased numbers of myeloid cells in the skin of ANTXR 1‐deficient mice are associated with reduced vascularity and increased skin fibrosis, suggesting a mechanism for hemangioma involution and replacement by fibrotic scars. Through controlling VEGF ‐A signalling and extracellular matrix synthesis, ANTXR 1 is emerging as a key regulator of skeletal and connective tissue development and homeostasis.