Regulatory mechanisms of skeletal and connective tissue development and homeostasis – lessons from studies of human disorders

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 VEGFR1, the VEGF decoy receptor, and suppress VEGF‐dependent VEGFR2 signalling by a mechanism that requires the matrix‐binding receptor Anthrax Toxin Receptor (ANTXR)1, VEGFR2, 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 VEGFR1 are extremely low and VEGFR2 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 ANTXR1, carrying a heterozygous Ala‐to‐Thr mutation, induces hemangioma‐like signalling in control endothelial cells; VEGF signalling is normalized when wild‐type ANTXR1 is overexpressed in hemangioma cells. These findings suggest that ANTXR1 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 ANTXR1, as well as knock‐in mice carrying the Ala‐to‐Thr ANTXR1 mutation, confirm that ANTXR1 functions as a suppressor of VEGF...
Source: International Journal of Experimental Pathology - Category: Pathology Authors: Tags: Review Article Source Type: research