Beta3 integrins are upregulated after vascular injury and modulate thrombospondin- and thrombin-induced proliferation of cultured smooth muscle cells.
BACKGROUND
Treatment with an antibody that binds beta3 integrins (abciximab; c7E3 Fab) at the time of coronary angioplasty decreases the need for repeat revascularization. Two potential mechanisms have been proposed to explain this effect: (1) inhibition of platelet aggregation or (2) interruption of ligand binding to beta3 integrins on the smooth muscle cell (SMC) surface. We examined the latter hypothesis by determining (1) if beta3 integrin expression is upregulated after vascular injury in the baboon, (2) if 7E3 binds beta3 integrins on cultured SMC, and (3) if beta3 integrin activation plays a role in proliferation of cultured SMC.


RESULTS
Results demonstrated that immunostaining for beta3 integrins was present in the neointima 1 week after balloon withdrawal injury of baboon brachial arteries and that beta3 integrin expression colocalized with alpha-actin-positive cells. In contrast, staining for beta3 integrins was undetectable in contralateral uninjured brachial arteries. 7E3 bound to cultured human aortic SMC with an affinity (KD=3.3 nmol/L) similar to 7E3 binding to endothelial cells or platelets. Cotreatment with 7E3 partially inhibited thrombospondin-induced or alpha-thrombin-induced proliferation but not PDGF-induced or serum-induced proliferation.


CONCLUSIONS
In summary, these studies demonstrate that vascular cell beta3 integrin expression is increased after injury, that 7E3 binds to cultured SMC with high affinity, and that beta3 activation is important for thrombospondin-induced or alpha-thrombin-induced proliferation. These results support the hypothesis that beta3 integrins play a role in SMC growth responses after balloon injury.
Stouffer
G A
GA
Sealy Center for Molecular Cardiology, University of Texas Medical Branch, Galveston 77555-1064, USA. stouffer@cardiology.utmb.edu
Hu
Z
Z
Sajid
M
M
Li
H
H
Jin
G
G
Nakada
M T
MT
Hanson
S R
SR
Runge
M S
MS
D000077284:Abciximab; D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism* / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism*; D001916:Brachial Artery / Q000293:injuries / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism* / Q000494:pharmacology; D039661:Integrin beta3; D016023:Integrins / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010215:Papio; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D015398:Signal Transduction; D013917:Thrombin / Q000494:pharmacology; D019699:Thrombospondins / Q000494:pharmacology; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D007140:Immunoglobulin Fab Fragments; D039661:Integrin beta3; D016023:Integrins; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D019699:Thrombospondins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D013917:Thrombin; D000077284:Abciximab