Tissue factor pathway inhibitor-2 is upregulated by vascular endothelial growth factor and suppresses growth factor-induced proliferation of endothelial cells.

Content Provider	Semantic Scholar
Author	Xu, Zhenhua Maiti, Debasish Kisiel, W. Jake Duh, Elia J.
Copyright Year	2006
Abstract	OBJECTIVE The purpose of this study is to investigate the expression and regulation of type-2 tissue factor pathway inhibitor (TFPI-2) in endothelial cells, as well as the regulation of human endothelial cell (EC) function by TFPI-2. METHODS AND RESULTS Real-time polymerase chain reaction (PCR) and Western blot analysis revealed that vascular endothelial growth factor (VEGF) induced both time- and dose-dependent increase in TFPI-2 mRNA and protein expression in endothelial cells. TFPI-2 mRNA expression was also significantly upregulated by IL-1beta, and modestly increased by both tumor necrosis factor (TNF)-alpha and fibroblast growth factor (FGF)-2, but not placental growth factor (PlGF). VEGF upregulation of TFPI-2 was dramatically reduced by inhibition of the MEK pathway. Administration of TFPI-2 protein suppressed both VEGF and FGF-2 stimulation of EC proliferation in a dose-dependent manner. A recombinant preparation of the first Kunitz-type domain of TFPI-2 (KD1) did not suppress growth factor stimulation of EC proliferation, suggesting a mechanism distinct from the proteinase inhibitory activity of TFPI-2. Exogenously added TFPI-2 protein suppressed VEGF-induced EC migration in 2 different assays. Recombinant wt-KD1 or the R24K mutant of KD1, but not the R24Q mutant, dramatically suppressed VEGF-induced EC migration. TFPI-2 protein, but not recombinant KD1, blocked VEGF-induced activation of both Akt and ERK1/2 in ECs. At higher doses, TFPI-2 protein blocked VEGFR2 activation. CONCLUSIONS Our data suggest that VEGF-upregulation of TFPI-2 expression in endothelial cells may represent a mechanism for negative feedback regulation and modulation of its pro-angiogenic action on endothelial cells. TFPI-2, or derivatives of TFPI-2, may be novel therapeutics for treatment of angiogenic disease processes.
Starting Page	033001
Ending Page	033001
Page Count	1
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://atvb.ahajournals.org/content/atvbaha/26/12/2819.full.pdf?download=true
Alternate Webpage(s)	http://atvb.ahajournals.org/content/atvbaha/26/12/2819.full.pdf
PubMed reference number	17023682v1
Volume Number	26
Issue Number	12
Journal	Arteriosclerosis, thrombosis, and vascular biology
Language	English
Access Restriction	Open
Subject Keyword	Angiogenic Process Endothelial Cells Endothelial Growth Factors Fibroblast Growth Factor Interleukin-1 beta MAPK-ERK Kinases Neoplasms PGF gene Paget's Disease, Mammary Placenta Polymerase Chain Reaction Proto-Oncogene Proteins c-akt Recombinants Therapeutic procedure Tumor Necrosis Factors Up-Regulation (Physiology) VEGF protein, human protein expression tissue-factor-pathway inhibitor 2
Content Type	Text
Resource Type	Article