Copyright © 2005, European Society of Cardiology
Reduced endothelial secretion and plasma levels of transforming growth factor-β1 in patients with hereditary hemorrhagic telangiectasia type 1
aCancer Research Program, Hospital for Sick Children, 555 University Avenue, Toronto, Canada, M5G 1X8.
bHeart and Stroke Lewar Center of Excellence, and Department of Immunology and Medical Biophysics, University of Toronto, Toronto, Canada
cInstitute for Agricultural, Rural and Environmental Health, University of Saskatchewan, Saskatoon, Canada
dDepartment of Pathology, Medical School, The University of Manchester, Manchester M13 9PT, UK
eProgram in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada
* Corresponding author. Cancer Research Program, Hospital for Sick Children, 555 University Avenue, Toronto, Canada, M5G 1X8. Tel.: +1 416 813 6258; fax: +1 416 813 6255. Email address: mablab{at}sickkids.ca
Objective: To determine if patients with hereditary hemorrhagic telangiectasia (HHT) show alterations in transforming growth factor (TGF)-β and its pathways.
Methods: Blood samples were obtained from HHT patients and controls, while endothelial cells were derived from umbilical veins of newborns (HUVEC) from HHT families. TGF-β1 in plasma, or secreted by HUVEC, and plasma endoglin levels were measured by ELISA. Cellular levels of endoglin and receptor Smad proteins were tested by metabolic labeling and immunoprecipitation, mRNA levels for endoglin and TGF-β1 by real-time PCR, and receptor Smad phosphorylation by Western blotting.
Results: TGF-β1 and endoglin plasma levels analyzed in 197 individuals showed an inverse correlation with age. Circulating levels of TGF-β1 were reduced in HHT1 patients (with Endoglin mutations) compared to control, but not in HHT2 patients (with ALK1 mutations). Endoglin levels were unchanged in plasma but decreased in activated monocytes and HUVEC with an HHT1 genotype. These HUVEC also expressed reduced levels of endoglin and TGF-β1 mRNA, secreted less TGF-β1, and showed normal receptor Smad expression and phosphorylation.
Conclusions: Decreased plasma TGF-β1 levels in HHT1 patients correlate with reduced production by endothelial cells. The lower endoglin expression in these cells may alter the regulation of TGF-β1 via Smad-independent pathways.
KEYWORDS cytokines; endothelial factors; endothelial receptors; hemostasis; signal transduction
Time for primary review 21 days
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