title: Regulatory mechanisms of anthrax toxin receptor 1-dependent vascular and connective tissue homeostasis.
abstract: It is well known that angiogenesis is linked to fibrotic processes in fibroproliferative diseases, but insights into pathophysiological processes are limited, due to lack of understanding of molecular mechanisms controlling endothelial and fibroblastic homeostasis. We demonstrate here that the matrix receptor anthrax toxin receptor 1 (ANTXR1), also known as tumor endothelial marker 8 (TEM8), is an essential component of these mechanisms. Loss of TEM8 function in mice causes reduced synthesis of endothelial basement membrane components and hyperproliferative and leaky blood vessels in skin. In addition, endothelial cell alterations in mutants are almost identical to those of endothelial cells in infantile hemangioma lesions, including activated VEGF receptor signaling in endothelial cells, increased expression of the downstream targets VEGF and CXCL12, and increased numbers of macrophages and mast cells. In contrast, loss of TEM8 in fibroblasts leads to increased rates of synthesis of fiber-forming collagens, resulting in progressive fibrosis in skin and other organs. Compromised interactions between TEM8-deficient endothelial and fibroblastic cells cause dramatic reduction in the activity of the matrix-degrading enzyme MMP2. In addition to insights into mechanisms of connective tissue homeostasis, our data provide molecular explanations for vascular and connective tissue abnormalities in GAPO syndrome, caused by loss-of-function mutations in ANTXR1. Furthermore, the loss of MMP2 activity suggests that fibrotic skin abnormalities in GAPO syndrome are, in part, the consequence of pathophysiological mechanisms underlying syndromes (NAO, Torg and Winchester) with multicentric skin nodulosis and osteolysis caused by homozygous loss-of-function mutations in MMP2.
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, USA. Electronic address: Tatiana_Besschetnova@hms.harvard.edu.
authors.forename: Tatiana Y
authors.initials: TY
authors.lastname: Besschetnova
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, USA.
authors.forename: Takaharu
authors.initials: T
authors.lastname: Ichimura
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, USA.
authors.forename: Negin
authors.initials: N
authors.lastname: Katebi
authors.affiliation: Tumor Angiogenesis Section, Mouse Cancer Genetics Program, National Cancer Institute (NCI), National Institutes of Health (NIH), Frederick, MD USA.
authors.forename: Brad
authors.initials: B
authors.lastname: St Croix
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, USA; Harvard-MIT Division of Health Sciences and Technology, USA.
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, USA; Department of Cell Biology, Harvard Medical School, USA. Electronic address: Bjorn_Olsen@hms.harvard.edu.
authors.forename: Bjorn R
authors.initials: BR
authors.lastname: Olsen
mesh_terms: D000505:Alopecia / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000848:Anodontia / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D018920:Coculture Techniques; D003094:Collagen / Q000378:metabolism; D003238:Connective Tissue / Q000196:embryology / Q000473:pathology / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006130:Growth Disorders / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins; D009154:Mutation; D015418:Optic Atrophies, Hereditary / Q000378:metabolism / Q000473:pathology; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000098:blood supply* / Q000196:embryology / Q000473:pathology
chemical_list: C523012:Antxr1 protein, mouse; D014408:Biomarkers, Tumor; D008840:Microfilament Proteins; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; D003094:Collagen; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse
keywords: Angiogenesis; Fibrosis; GAPO syndrome; Hemangioma; MMP2