© 2000 American Heart Association, Inc.
Vascular Biology |
Vascular Endothelial Cells and Smooth Muscle Cells Differ in Expression of Fas and Fas Ligand and in Sensitivity to Fas Ligand–Induced Cell Death
Implications for Vascular Disease and Therapy
From the Division of Cardiovascular Research, St. Elizabeth’s Medical Center (M.S., T.S., K.W.), and the Program in Cell, Molecular, and Developmental Biology, Sackler School of Biomedical Sciences (K.W.), Tufts University, Boston, Mass; and the Department of Cardiovascular Medicine, Graduate School of Medicine (M.S.), University of Tokyo, Tokyo, Japan.
Correspondence to Dr Kenneth Walsh, Division of Cardiovascular Research, St. Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail kwalsh{at}opal.tufts.edu
Abstract—Fas ligand (FasL) is a
death factor that induces apoptosis in cells bearing its
receptor, Fas. Fas and FasL have been detected in the vessel wall, and
it has been proposed that Fas-mediated apoptosis has a role in
physiological and pathological cell turnover in the
vasculature. Here, we evaluated the expression of Fas in the presence
and absence of cytokines on both endothelial
cells (ECs) and vascular smooth muscle cells (VSMCs). We also examined
the sensitivity of ECs and VSMCs to Fas-mediated apoptosis
induced by exposure to multiple Fas agonists: soluble FasL, anti-Fas
antibody, and membrane-bound FasL resulting from transduction with a
replication-defective adenovirus expressing FasL (Adeno-FasL).
Cell-surface FasL expression was detected on human ECs with the use of
4 anti-FasL antibodies, whereas cell-surface FasL expression was not
detected on VSMCs. Unstimulated ECs expressed relatively low levels of
Fas, but expression was upregulated after treatment with tumor necrosis
factor-
(TNF-) or interferon gamma (IFN-
). In contrast, VSMCs
expressed relatively high levels of Fas, and treatment with TNF- or
IFN- induced little or no upregulation under the conditions of these
assays. ECs were resistant to death after exposure to soluble
FasL or agonist anti-Fas antibody and also after infection with
Adeno-FasL in the presence or absence of cytokine treatment. In
contrast, VSMCs remained viable in the presence of soluble FasL or
agonist anti-Fas antibody, but they underwent apoptosis after
infection with Adeno-FasL. IFN- enhanced Adeno-FasL-induced death of
VSMCs, but TNF- did not. These findings provide insights about the
potential role of Fas-mediated apoptosis in the vessel wall and
suggest strategies to treat proliferative vascular diseases by
exploiting the differential sensitivity of ECs and VSMCs to
FasL-induced cell death.
Key Words: Fas • adenovirus • smooth muscle cells • endothelial cells • apoptosis
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