title: Early atheroma-derived agonists of peroxisome proliferator-activated receptor-γ trigger intramedial angiogenesis in a smooth muscle cell-dependent manner.
abstract: BACKGROUND
  Neovascularization favors intraplaque hemorrhage and plaque rupture. Development of therapeutic strategies against atheromatous angiogenesis requires elucidation of its initiating factors.
  
  
  OBJECTIVE
  We investigated the contribution of smooth muscle cells (SMCs) and atheroma-derived lipids to the initiation of atheroma-associated neoangiogenesis.
  
  
  RESULTS
  Forty human aortic segments, each harvested from a different donor, were classified as healthy or as bearing early atheromatous lesions, including fatty streaks and fibrolipidic atheroma, according to their histological features. Immunostaining for blood vessels and vascular endothelial growth factor-A (VEGF-A), as well as measurement of VEGF-A protein and mRNA levels by ELISA and real-time PCR, revealed that angiogenesis and VEGF-A production were enhanced in the medial layer of atheromatous aortas. The intramedial vessel density and invasiveness and the production of VEGF-A by medial SMCs were indeed increased in atheromatous aortas compared with healthy aortas. Furthermore, intimal layers of atheromatous aortas were enriched in soluble lipid mediators capable of inducing a sustained increase in VEGF-A production by medial SMCs, turning these cells into potent inducers of angiogenesis when incorporated into mouse Matrigel implants. Both effects were inhibited by the peroxisome proliferator-activated receptor-γ inhibitor GW9662 and mimicked by its agonist, rosiglitazone.
  
  
  CONCLUSIONS
  We show that VEGF-A production is upregulated in medial SMCs of human atheromatous aortas and that peroxisome proliferator-activated receptor-γ agonists derived from early intimal lesions are likely to contribute to this phenotypic change. Our findings suggest that medial SMCs are central organizers of an angiogenic response initiated by the subendothelial accumulation of atherogenic lipids.
authors: Univ Paris Diderot, Sorbonne Paris Cité, Inserm UMR698, Paris, France.HHbenoit.ho-tin-noe@inserm.frHH
authors: Benoît
authors: B
authors: Ho-Tin-Noé
authors: Julien
authors: J
authors: Le Dall
authors: Delphine
authors: D
authors: Gomez
authors: Liliane
authors: L
authors: Louedec
authors: Roger
authors: R
authors: Vranckx
authors: Morad
authors: M
authors: El-Bouchtaoui
authors: Luc
authors: L
authors: Legrès
authors: Olivier
authors: O
authors: Meilhac
authors: Jean-Baptiste
authors: JB
authors: Michel
mesh_terms: D000813:Anilides / Q000494:pharmacology; D001011:Aorta / Q000378:metabolism / Q000503:physiopathology*; D002478:Cells, Cultured; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000503:physiopathology*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D047495:PPAR gamma; D045162:Thiazolidinediones; D042461:Vascular Endothelial Growth Factor A; D000077154:Rosiglitazone