P. Carmeliet et al., VASCULAR WOUND-HEALING AND NEOINTIMA FORMATION INDUCED BY PERIVASCULAR ELECTRIC INJURY IN MICE, The American journal of pathology, 150(2), 1997, pp. 761-776
Vascular interventions for atherothrombotic disease frequently induce
neointima formation, which can contribute to restenosis of blood vesse
ls. As the molecular mechanisms of this process remain largely unknown
, quantitative models of arterial injury in transgenic animals may be
useful to study this process at the genetic level. Here, an injury mod
el is proposed in which surgically exposed femoral arteries in mice we
re injured perivascularly via a single delivery of an electric current
. Transmission electron microscopy, light microscopy, and immunohistoc
hemistry revealed that electric injury destroyed all medial smooth mus
cle cells, denuded the injured segment of intact endothelium, and tran
siently induced platelet-rich mural thrombosis. A vascular wound-heali
ng response resulted that was characterized by degradation of the mura
l thrombus, transient infiltration of the vessel wall by inflammatory
cells, and progressive removal of the necrotic debris. Topographic ana
lysis revealed repopulation of the media and accumulation in the neoin
tima of smooth muscle cells originating from the uninjured borders and
progressing into the necrotic center. Within 3 weeks after injury, a
neointima of 0.026 +/- 0.003 mm(2) (n = 7 arteries) was formed that co
ntained a maximum of 12 +/- 1 layers of smooth muscle alpha-actin-immu
noreactive cells. Evans blue staining in five electrically injured art
eries revealed a denuded distance of 2.8 +/- 0.2 mm immediately after
injury, which became progressively re-endothelialized from the uninjur
ed borders to 2.2 +/- 0.08 mm (P = 0.013 vs freshly injured by analysi
s of variance), 0.8 +/- 0.22 mm (P < 0.001), and 0.005 +/- 0.003 mm (P
< 0.001) within 2, 7, and 14 days after injury, respectively. Analysi
s of 5'-bromo-2'-deoxyuridine incorporation revealed that a maximum 35
+/- 10% endothelial cells proliferated within 2 days after injury and
that in the media and neointima, a maximum of, respectively, 12 +/- 2
% and 18 +/- 3% smooth muscle cells proliferated within 2 weeks after
injury. Thus, electric injury of arteries provides a model of vascular
wound healing with arterial neointima formation and re-endothelializa
tion that may be useful for the genetic analysis of its molecular mech
anisms in transgenic mice.