From the sections of Cardiology (N.M., J.G., S.E.F., C.M.H.N., D.C.
Crossman) and Interventional Cardiology (N.M., J.G., C.M.H., L.S., D.C.
Cumberland), University of Sheffield, Clinical Sciences Centre, Northern
General Hospital, Sheffield, UK; and the Sheffield Kidney Institute (G.L.T.),
Northern General Hospital, Sheffield, UK.
Correspondence to Dr Nadim Malik, Cardiovascular Medicine, University of Sheffield, Clinical Sciences Centre, Northern General Hospital, Herries Road, Sheffield S5 7AU, UK. E-mail n.malik{at}sheffield.ac.uk
Background—Angioplasty initiates
a number of responses in the vessel wall including cellular migration,
proliferation, and matrix accumulation, all of which contribute to
neointima formation and restenosis. Cellular
homeostasis within a tissue depends on the balance between cell
proliferation and apoptosis.
Methods and Results—Profiles of apoptosis and
proliferation were therefore examined in a porcine PTCA injury model
over a 28-day period. Forty-two arteries from 21 pigs, harvested at the
site of maximal injury at 1, 6, and 18 hours, and 3, 7, 14, and 28 days
after PTCA, were examined (n=3 animals per time point). Uninjured
arteries were used as controls. Apoptosis was demonstrated by
the terminal uridine nick-end labeling (TUNEL) method, transmission
electron microscopy (TEM), and DNA fragmentation. Cells traversing the
cell cycle were identified by immunostaining for
proliferating cell nuclear antigen (PCNA). Apoptosis was not
detected in control vessels at all time points nor at 28 days after
PTCA. Apoptotic cells were identified at all early time points
with a peak at 6 hours (5.1±0.26%; compared to uninjured artery,
P<0.001) and confirmed by characteristic DNA ladders
and TEM findings. Regional analysis showed apoptosis
within the media, adventitia, and neointima peaked at 18
hours, 6 hours, and 7 days after PTCA, respectively. In comparison,
PCNA staining peaked at 3 days after PTCA (7.16±0.29%; compared to
1.78±0.08% PCNA-positive cells in the uninjured artery,
P<0.001). Profiles of apoptosis and cell
proliferation after PTCA were discordant in all layers of the artery
except the neointima. These profiles also differed between
traumatized and nontraumatized regions of the arterial
wall. Immunostaining with cell-type specific markers
and TEM analysis revealed that apoptotic cells included
vascular smooth muscle cells (VSMCs), inflammatory cells, and
adventitial fibroblasts.
Conclusions—These results suggest that the profile of
apoptosis and proliferation after PTCA is regional and cell
specific, and attempts to modulate either of these events for
therapeutic benefit requires recognition of these differences.
© 1998 American Heart Association, Inc.
Basic Science Reports
Apoptosis and Cell Proliferation After Porcine Coronary Angioplasty
Key Words: angioplasty • apoptosis • cell proliferation • restenosis
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