title: Angiotensin-converting enzyme inhibition abolishes medial smooth muscle PDGF-AB biosynthesis and attenuates cell proliferation in injured carotid arteries: relationships to neointima formation.
abstract: BACKGROUND
  ACE inhibitors can attenuate the development of intimal fibrocellular lesions after balloon catheter vessel injury, but the mechanisms responsible are unknown.
  
  
  RESULTS
  To evaluate how basic fibroblast growth factor (FGF-2) and the platelet-derived growth factor (PDGF) isoforms are affected by ACE inhibition in injured rat carotid arteries in relation to smooth muscle cell (SMC) proliferation, we examined the effects of oral perindopril on FGF-2 and PDGF isoform levels in carotid arteries 2 days after balloon catheter injury. [3H]Thymidine incorporation into medial and intimal SMCs was also assessed. Uninjured vessels contained two forms of FGF-2, with molecular weights of 18 and 22 kD, and PDGF-AA. Two days after injury, FGF-2 and PDGF-AA levels were markedly reduced, but high levels of PDGF-AB became apparent when the SMCs were proliferating. Perindopril completely abolished the biosynthesis of PDGF-AB but had little effect on residual FGF-2. This was accompanied by a 25% reduction in medial SMC proliferation. Neointimal cell proliferation 10 days after injury was unaffected by perindopril, although neointima size was reduced by 30%. Commencing perindopril treatment 4 days after the injury confirmed that early events associated with effects on medial SMCs were the major contributors to the attenuated neointimal lesions.
  
  
  CONCLUSIONS
  The ability of ACE inhibitors such as perindopril to attenuate neointima formation and growth in balloon catheter-injured rat carotid arteries is dependent on early events in the media, the inhibition of SMC PDGF-AB biosynthesis and attenuation of proliferation. Neointima formation in similarly injured vessels containing SMCs that are either unresponsive to PDGF-AB or exhibit an ACE-independent profile of growth factor biosynthesis responses may account for the ineffectiveness of ACE inhibition in some species.
authors.affiliation: Cell Biology Laboratory, Baker Medical Research Institute and Alfred Hospital, Victoria, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Wong
authors.forename: C
authors.initials: C
authors.lastname: Rauhöft
authors.forename: R J
authors.initials: RJ
authors.lastname: Dilley
authors.forename: A
authors.initials: A
authors.lastname: Agrotis
authors.forename: G L
authors.initials: GL
authors.lastname: Jennings
authors.forename: A
authors.initials: A
authors.lastname: Bobik
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism* / Q000473:pathology; D020212:Carotid Artery Injuries; D002404:Catheterization; D002455:Cell Division / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D007536:Isomerism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D020913:Perindopril; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects / Q000254:growth & development
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; C095477:platelet-derived growth factor AB; D016222:Fibroblast Growth Factor 2; D020913:Perindopril