Local delivery of vascular endothelial growth factor accelerates reendothelialization and attenuates intimal hyperplasia in balloon-injured rat carotid artery.
BACKGROUND
Most strategies designed to reduce restenosis by the use of pharmacological or biological reagents involve direct inhibition of vascular smooth muscle cell (SMC) proliferation. Alternatively, SMC proliferation might be indirectly inhibited if reendothelialization could be specifically facilitated at sites of balloon-induced arterial injury. Accordingly, we investigated the hypothesis that application of an endothelial cell (EC)-specific mitogen to a freshly denuded intimal surface could accelerate reendothelialization and thereby attenuate intimal hyperplasia.


RESULTS
The left carotid artery of 31 Sprague-Dawley rats was subjected to balloon injury, after which 16 rats were treated with a 30-minute incubation with 100 micrograms of vascular endothelial growth factor (VEGF), an EC-specific mitogen. Control animals (n = 15) received a 30-minute incubation with 0.9% saline. At 2 weeks after balloon injury, carotid artery reendothelialization was markedly superior in the VEGF-treated group compared with the control group (14.59 +/- 1.12 versus 7.96 +/- 0.51 mm2, P < 0.005). The extent of reendothelialization measured at 4 weeks after balloon injury remained superior for arteries treated with VEGF (18.04 +/- 0.90 mm2) versus saline (13.42 +/- 0.84 mm2, P < .005). Neointimal thickening was correspondingly attenuated to a statistically significant degree in arteries treated with VEGF versus the control group at both the 2-week and 4-week time points. Immunostaining for proliferating cell nuclear antigen (PCNA) disclosed a threefold increase in PCNA-positive cells in the neointima of control arteries versus VEGF-treated arteries at 2 weeks after injury.


CONCLUSIONS
Application of VEGF, an EC-specific growth regulatory molecule, may be effectively used in vivo to promote reendothelialization and thereby indirectly attenuate neointimal thickening due to SMC proliferation.
Asahara
T
T
Department of Medicine (Cardiology), St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA.
Bauters
C
C
Pastore
C
C
Kearney
M
M
Rossow
S
S
Bunting
S
S
Ferrara
N
N
Symes
J F
JF
Isner
J M
JM
D000818:Animals; D020212:Carotid Artery Injuries; D017536:Carotid Artery, Common / Q000648:ultrastructure; D002404:Catheterization; D016228:Endothelial Growth Factors / Q000008:administration & dosage* / Q000627:therapeutic use; D004730:Endothelium, Vascular / Q000502:physiology*; D006965:Hyperplasia; D008222:Lymphokines / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D008854:Microscopy, Electron; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration / Q000502:physiology; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D018809:Proliferating Cell Nuclear Antigen; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors