Adenoviral activin a expression prevents intimal hyperplasia in human and murine blood vessels by maintaining the contractile smooth muscle cell phenotype.
Activin A alters the characteristics of human arterial smooth muscle cells (SMCs) toward a contractile, quiescent phenotype. We hypothesize that activin A may prevent SMC-rich neointimal hyperplasia. Here, we study the effect of adenovirus-mediated expression of activin A on neointima formation in vitro and in vivo. Human saphenous vein organ cultures, in which a neointima is formed spontaneously, were infected either with activin A- or lacZ-adenovirus. Activin A-overexpression reduces neointima formation by 78%, whereas no significant reduction was observed after control infection. In addition, the effect of activin A on neointima formation was assessed in vivo in mice with cuffed femoral arteries. In activin A adenovirus-infected mice (IV injection), neointimal hyperplasia is reduced by 77% compared with the SMC-rich neointima in mock-infected or in noninfected mice. Cultured human saphenous vein SMCs and murine aorta SMCs were incubated with activin A and an increased expression of SM22alpha and SM alpha-actin mRNA, and SM alpha-actin protein was demonstrated. Laser-capture microdissection on sections of cuffed murine arteries and subsequent real-time RT-PCR established in vivo induction of SM alpha-actin mRNA in the media of activin A-treated mice. In summary, activin A inhibits neointima formation in vitro and in vivo by preventing SMC dedifferentiation.
Engelse
Marten A
MA
Academic Medical Center, University of Amsterdam, Department of Biochemistry, Amsterdam, The Netherlands.
Lardenoye
JanWillem H P
JH
Neele
Jolanda M
JM
Grimbergen
Jos M
JM
De Vries
Margreet R
MR
Lamfers
Martine L M
ML
Pannekoek
Hans
H
Quax
Paul H A
PH
De Vries
Carlie J M
CJ
D028341:Activins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D005263:Femoral Artery / Q000166:cytology / Q000473:pathology; D005822:Genetic Vectors; D006801:Humans; D006965:Hyperplasia; D028322:Inhibin-beta Subunits / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D009119:Muscle Contraction; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D009924:Organ Culture Techniques; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis; D012501:Saphenous Vein / Q000033:anatomy & histology / Q000166:cytology; D017539:Tunica Intima / Q000473:pathology
D009124:Muscle Proteins; D012333:RNA, Messenger; C422405:activin A; D028341:Activins; D028322:Inhibin-beta Subunits