title: Glucagon-Like Peptide-1 Receptor Activation Does not Affect Re-Endothelialization but Reduces Intimal Hyperplasia via Direct Effects on Smooth Muscle Cells in a Nondiabetic Model of Arterial Injury.
abstract: Diabetic patients have an increased risk of restenosis and late stent thrombosis after angioplasty, i.e. complications that are related to a defective re-endothelialization. Exendin-4, a stable glucagon-like peptide (GLP)-1 receptor agonist, has been suggested to influence the formation of intimal hyperplasia and to increase endothelial cell proliferation in vitro. Thus, the aim of this study was to investigate the mechanisms by which treatment with exendin-4 could influence re-endothelialization and intimal hyperplasia after vascular injury.
  
  
  METHODS
  Sprague-Dawley rats were subjected to balloon injury of the left common carotid artery and treated for 4 weeks with exendin-4 or vehicle. Intimal hyperplasia and vessel wall elasticity were monitored noninvasively by high-frequency ultrasound, and re-endothelialization was evaluated upon sacrifice using Evans blue dye.
  
  
  CONCLUSIONS
  Exendin-4 selectively reduced the proliferation of smooth muscle cells (SMCs) and intimal hyperplasia in vivo without affecting the re-endothelialization process, but treatment with exendin-4 improved arterial wall elasticity. Our data also show that exendin-4 significantly decreased the proliferation and increased the apoptosis of SMCs in vitro, effects that appear to be mediated through cAMP signaling and endothelial nitric oxide synthase following GLP-1 receptor activation. Together, these effects of exendin-4 are highly desirable and may lead to an improved outcome for patients undergoing vascular interventions.
authors.affiliation: Department of Clinical Science and Education, Södersjukhuset, Stockholm, Sweden.
authors.forename: Linnea
authors.initials: L
authors.lastname: Eriksson
authors.forename: Robert
authors.initials: R
authors.lastname: Saxelin
authors.forename: Samuel
authors.initials: S
authors.lastname: Röhl
authors.forename: Joy
authors.initials: J
authors.lastname: Roy
authors.forename: Kenneth
authors.initials: K
authors.lastname: Caidahl
authors.forename: Thomas
authors.initials: T
authors.lastname: Nyström
authors.forename: Ulf
authors.initials: U
authors.lastname: Hedin
authors.forename: Anton
authors.initials: A
authors.lastname: Razuvaev
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000473:pathology; D017536:Carotid Artery, Common / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D000077270:Exenatide; D005230:Fatty Acids, Nonesterified / Q000097:blood; D000067757:Glucagon-Like Peptide-1 Receptor; D006965:Hyperplasia; D007328:Insulin / Q000097:blood; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists* / Q000502:physiology; D012038:Regeneration / Q000187:drug effects; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology; D059289:Vascular Stiffness / Q000187:drug effects; D014688:Venoms / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000077270:Exenatide; D000242:Cyclic AMP; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat