title: Atheroprotective role of Caveolin-1 and eNOS in an innovative transplantation model is mainly mediated by local effects.
abstract: Endothelial dysfunction is crucial in the initiation of atherosclerosis, which is associated with a lack of nitric oxide. The endothelial NO synthase (eNOS) is responsible for constitutive synthesis of NO and inhibited by caveolin-1 (Cav1). In the current study, we examined the influence on intima formation through single and combined deletion of eNOS and Cav1 with a focus on differentiation of local and systemic effects. A sex-mismatch transplantation of denudated aortae from female C57BL/6n (WT), Cav1-/-, eNOS-/-and Cav1-/-/eNOS-/-(C/e--/--) mice in common carotid artery of male WT mice was performed. After six weeks on Western-type diet, the aortae were explanted and intimal lesions were quantified by determining the intima-media-ratio (IMR). Significantly larger plaques were observed in all knockout mice compared to WT. The highest IMR was detected in Cav1-/-arteries associated with an increased expression of α-smooth muscle actin (αSMA) and the proliferating cell nuclear antigen (PCNA). Both were reduced in aortae from C/e--/--. Galectin-3 (Gal3) immunostaining revealed only small infiltrations of macrophages. Systemic cell invasion was detected by Y chromosome fluorescence in situ hybridization (Y-FISH), which showed only small numbers of systemic cells and no differences between the genotypes. Loss of Cav1 increased vascular lesion by enhancing neointimal proliferation. The combined loss of Cav1 and eNOS, compared to Cav1-/-, lowered intima formation, suggesting an increasing effect of eNOS in the absence of Cav1 on vascular lesion. Furthermore, these effects seem to be mediated by local cells rather than by systemically invaded ones.
authors.affiliation: Technische Universität Dresden, Heart Centre Dresden University Hospital, Germany. Electronic address: johannes.mierke@mailbox.tu-dresden.de.
authors.forename: Johannes
authors.initials: J
authors.lastname: Mierke
authors.affiliation: Technische Universität Dresden, Heart Centre Dresden University Hospital, Germany.
authors.forename: Marian
authors.initials: M
authors.lastname: Christoph
authors.affiliation: Technische Universität Dresden, Heart Centre Dresden University Hospital, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Pfluecke
authors.affiliation: Technische Universität Dresden, Heart Centre Dresden University Hospital, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Jellinghaus
authors.affiliation: Technische Universität Dresden, Heart Centre Dresden University Hospital, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Wunderlich
authors.affiliation: Technische Universität Dresden, Heart Centre Dresden University Hospital, Germany.
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Strasser
authors.affiliation: Technische Universität Dresden, Heart Centre Dresden University Hospital, Germany.
authors.forename: Karim
authors.initials: K
authors.lastname: Ibrahim
authors.affiliation: Technische Universität Dresden, Heart Centre Dresden University Hospital, Germany.
authors.forename: David M
authors.initials: DM
authors.lastname: Poitz
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology / Q000637:transplantation*; D017536:Carotid Artery, Common / Q000473:pathology / Q000601:surgery*; D016893:Carotid Stenosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D051242:Caveolin 1 / Q000235:genetics*; D005260:Female; D055786:Gene Knockout Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058426:Neointima / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D017539:Tunica Intima / Q000473:pathology; D058017:Vascular Grafting / Q000009:adverse effects* / Q000379:methods
chemical_list: D051242:Caveolin 1; D052250:Nitric Oxide Synthase Type III
keywords: Atherosclerosis; Caveolin-1; Endothelial NO synthase; Intima formation; Restenosis; Transplantation