Reduced intimal thickening following alpha(v)beta3 blockade is associated with smooth muscle cell apoptosis.
The adhesion integrin alpha(v)beta3 is expressed by both activated endothelial cells (ECs) and smooth muscle cells (SMCs). Peptide and antibody antagonists of alpha(v)beta3 have been shown to block angiogenesis by initiating unscheduled programmed cell death of proliferating ECs. The present study was designed to determine if antagonism of alpha(v)beta3 immediately following balloon injury might similarly lead to programmed cell death among activated SMCs, and thereby inhibit intimal thickening. LM609, a monoclonal antibody antagonist of alpha(v)beta3, was administered locally and/or systemically immediately after balloon angioplasty in a rabbit model of vascular injury. Immunohistochemical studies documented that LM609, even when administered systemically, localized to sites of vascular injury. LM609 administered immediately following balloon injury of the external iliac artery markedly reduced intimal thickening at 2 and 4 wk post-injury. Apoptosis was abundant where balloon injury resulted in expression of alpha(v)beta3. At both 2 and 4 wk, re-endothelialization at the site of balloon injury was not retarded in LM609-treated rabbits versus controls. Thus, blockade of alpha(v)beta3 inhibits intimal thickening when administered immediately following balloon injury. This favorable impact on neointimal thickening is associated with apoptosis of activated SMCs expressing alpha(v)beta3. These findings may explain the reduction in restenosis observed clinically following beta3 integrin blockade.
van der Zee
R
R
Department of Biomedical Research, St. Elizabeth's Medical Center, Tufts University, School of Medicine, Boston, MA 02135-2997, USA.
Murohara
T
T
Passeri
J
J
Kearney
M
M
Cheresh
D A
DA
Isner
J M
JM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D017209:Apoptosis; D002404:Catheterization / Q000009:adverse effects; D004727:Endothelium / Q000033:anatomy & histology / Q000502:physiology; D009130:Muscle, Smooth / Q000033:anatomy & histology / Q000502:physiology*; D011817:Rabbits; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology*; D013997:Time Factors; D017539:Tunica Intima / Q000502:physiology*
D000911:Antibodies, Monoclonal; D019030:Receptors, Vitronectin