|Tissue factor pathway inhibitor blocks angiogenesis via its carboxyl terminus.|
|PMID: 22223730 Owner: NLM Status: MEDLINE|
|OBJECTIVE: Tissue factor pathway inhibitor (TFPI) is the primary regulator of the tissue factor (TF) coagulation pathway. As such, TFPI may regulate the proangiogenic effects of TF. TFPI may also affect angiogenesis independently of TF, through sequences within its polybasic carboxyl terminus (TFPI C terminus [TFPIct]). We aimed to determine the effects of TFPI on angiogenesis and the role of TFPIct.
METHODS AND RESULTS: Transgenic overexpression of TFPI attenuated angiogenesis in the murine hindlimb ischemia model and an aortic sprout assay. In vitro, TFPI inhibited endothelial cell migration. Peptides within the human TFPIct inhibited endothelial cell cord formation and migration in response to vascular endothelial growth factor (VEGF) 165 but not VEGF121. Furthermore, exposure to human TFPIct inhibited the phosphorylation of VEGF receptor 2 at residue Lys951, a residue known to be critical for endothelial cell migration. Finally, systemic delivery of a murine TFPIct peptide inhibited angiogenesis in the hindlimb model.
CONCLUSION: These data demonstrate an inhibitory role for TFPI in angiogenesis that is, in part, mediated through peptides within its carboxyl terminus. In addition to its known role as a TF antagonist, TFPI, via its carboxyl terminus, may regulate angiogenesis by directly blocking VEGF receptor 2 activation and attenuating the migratory capacity of endothelial cells.
|Eric W Holroyd; Sinny Delacroix; Katarina Larsen; Adriana Harbuzariu; Peter J Psaltis; Ling Wang; Shuchong Pan; Thomas A White; Tyra A Witt; Laurel S Kleppe; Cheryl S Mueske; Debabrata Mukhopadhyay; Robert D Simari|
|Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-01-05|
|Title: Arteriosclerosis, thrombosis, and vascular biology Volume: 32 ISSN: 1524-4636 ISO Abbreviation: Arterioscler. Thromb. Vasc. Biol. Publication Date: 2012 Mar|
|Created Date: 2012-02-20 Completed Date: 2012-04-13 Revised Date: 2013-06-26|
Medline Journal Info:
|Nlm Unique ID: 9505803 Medline TA: Arterioscler Thromb Vasc Biol Country: United States|
|Languages: eng Pagination: 704-11 Citation Subset: IM|
|Division of Cardiovascular Diseases, Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.|
|APA/MLA Format Download EndNote Download BibTex|
Disease Models, Animal
Heparin / metabolism
Human Umbilical Vein Endothelial Cells / metabolism
Ischemia / genetics, metabolism*, physiopathology
Lipoproteins / chemistry, deficiency, genetics, metabolism*, pharmacology
Mice, Inbred C57BL
Microfilament Proteins / genetics
Muscle Proteins / genetics
Muscle, Skeletal / blood supply*
Neovascularization, Physiologic* / drug effects
Peptides / pharmacology
Promoter Regions, Genetic
Protein Structure, Tertiary
Vascular Endothelial Growth Factor Receptor-2 / metabolism
|HL 65191/HL/NHLBI NIH HHS; R01 HL065191-10/HL/NHLBI NIH HHS; R01 HL070567/HL/NHLBI NIH HHS|
|0/Angiogenesis Inhibitors; 0/Lipoproteins; 0/Microfilament Proteins; 0/Muscle Proteins; 0/Peptides; 0/Tagln protein, mouse; 0/lipoprotein-associated coagulation inhibitor; 9005-49-6/Heparin; EC 22.214.171.124/Vascular Endothelial Growth Factor Receptor-2|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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