Functional relevance of tetraspanin CD9 in vascular smooth muscle cell injury phenotypes: a novel target for the prevention of neointimal hyperplasia.
Vascular smooth muscle cell (VSMC) migration and proliferation are critical events in the development of neointima following vascular injury. In this study, we found that CD9 is constitutively expressed in the VSMC of the neointima of injured carotid arteries. The in vitro migration and proliferation of human coronary artery smooth muscle (hCASM) cells were reduced by 40% and 63%, respectively, by treatment with a CD9 specific monoclonal antibody mAb7 when compared to control antibody treatment. In a mouse carotid ligation injury model, a single application of a neutralizing anti-mouse CD9 antibody resulted in a 31% (day 14, n=8, p<0.05), and 32% (day 28, n=5, p<0.01) reduction in neointima formation. In support of these findings, exogenous expression of human CD9 by CD9-adenoviral transduction led to 43% increases in neointima (p<0.05, n=6). Upon investigation of the mechanisms underlying CD9 mediated VSMC phenotypic events we found that integrin alpha5beta1 was a constitutive partner of CD9 and that CD9 significantly augmented PI-3 kinase dependent Akt phosphorylation. Furthermore, enhanced Akt phosphorylation was attenuated by mAb7 binding. Cumulatively, a functional link between CD9, alpha5beta1, PI3-K/Akt activity and enhanced VSMC migratory and proliferative phenotypes has been demonstrated. These studies suggest that agents that modulate CD9 mediated VSMC phenotypes may emerge as novel strategies for the treatment of abnormal vascular injury response.
Kotha
Jayaprakash
J
Vascular Biology Center of Excellence, University of Tennessee Health Science Center, Memphis, 38163, USA.
Zhang
Chunxiang
C
Longhurst
Celia M
CM
Lu
Yi
Y
Jacobs
Jonathan
J
Cheng
Yunhui
Y
Jennings
Lisa K
LK
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D003331:Coronary Vessels / Q000473:pathology; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D060245:Tetraspanin 29; D059470:Tetraspanins
D015703:Antigens, CD; C554869:CD9 protein, human; C554870:Cd9 protein, mouse; D039081:Integrin alpha5beta1; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C534243:TSPAN9 protein, human; D060245:Tetraspanin 29; D059470:Tetraspanins; D051057:Proto-Oncogene Proteins c-akt