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Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 2936-2944
E1 E4+ Adenoviral Gene Transfer Vectors
Function as a "Pro-Life" Signal to Promote Survival of
Primary Human Endothelial Cells
Ramachandran Ramalingam,
Shahin Rafii,
Stefan Worgall,
Douglas E. Brough, and
Ronald G. Crystal
From Division of Pulmonary and Critical Care Medicine, and Division
of Hematology-Oncology, The New York Hospital-Cornell Medical Center,
New York, NY, and GenVec, Inc, Rockville, MD.
Although endothelial cells are quiescent and long-lived in vivo,
when they are removed from blood vessels and cultured in vitro they die
within days to weeks. In studies of the interaction of
E1 E4+ replication-deficient adenovirus
(Ad) vectors and human endothelium, the cells remained quiescent and
were viable for prolonged periods. Evaluation of these cultures showed
that E1E4+ Ad vectors provide an
"antiapoptotic" signal that, in association with an increase in
the ratio of Bcl2 to Bax levels, induces the endothelial cells to enter
a state of "suspended animation," remaining viable for at least
30 days, even in the absence of serum and growth factors. Although the
mechanisms initiating these events are unclear, the antiapoptoic signal
requires the presence of E4 genes in the vector genome, suggesting that
one or more E4 open reading frames of subgroup C Ad initiate a
"pro-life" program that modifies cultured endothelial cells to
survive for prolonged periods.
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