title: Macrophage-derived IL-18 and increased fibrinogen deposition are age-related inflammatory signatures of vascular remodeling.
abstract: Aging has been associated with pathological vascular remodeling and increased neointimal hyperplasia. The understanding of how aging exacerbates this process is fundamental to prevent cardiovascular complications in the elderly. This study proposes a mechanism by which aging sustains leukocyte adhesion, vascular inflammation, and increased neointimal thickness after injury. The effect of aging on vascular remodeling was assessed in the rat balloon injury model using microarray analysis, immunohistochemistry, and LINCOplex assays. The injured arteries in aging rats developed thicker neointimas than those in younger animals, and this significantly correlated with a higher number of tissue macrophages and increased vascular IL-18. Indeed, IL-18 was 23-fold more abundant in the injured vasculature of aged animals compared with young rats, while circulating levels were similar in both groups of animals. The depletion of macrophages in aged rats with clodronate liposomes ameliorated vascular accumulation of IL-18 and significantly decreased neointimal formation. IL-18 was found to inhibit apoptosis of vascular smooth muscle cells (VSMC) and macrophages, thus favoring both the formation and inflammation of the neointima. In addition, injured arteries of aged rats accumulated 18-fold more fibrinogen-γ than those of young animals. Incubation of rat peritoneal macrophages with immobilized IL-18 increased leukocyte adhesion to fibrinogen and suggested a proinflammatory positive feedback loop among macrophages, VSMC, and the deposition of fibrinogen during neointimal hyperplasia. In conclusion, our data reveal that concentration changes in vascular cytokine and fibrinogen following injury in aging rats contribute to local inflammation and postinjury neointima formation.
authors.affiliation: Department of Surgery and Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, Florida;
authors.forename: Luis
authors.initials: L
authors.lastname: Rodriguez-Menocal
authors.forename: Mohd Hafeez
authors.initials: MH
authors.lastname: Faridi
authors.forename: Laisel
authors.initials: L
authors.lastname: Martinez
authors.forename: Lina A
authors.initials: LA
authors.lastname: Shehadeh
authors.forename: Juan C
authors.initials: JC
authors.lastname: Duque
authors.forename: Yuntao
authors.initials: Y
authors.lastname: Wei
authors.forename: Annia
authors.initials: A
authors.lastname: Mesa
authors.forename: Angela
authors.initials: A
authors.lastname: Pena
authors.forename: Vineet
authors.initials: V
authors.lastname: Gupta
authors.forename: Si M
authors.initials: SM
authors.lastname: Pham
authors.forename: Roberto I
authors.initials: RI
authors.lastname: Vazquez-Padron
mesh_terms: D000367:Age Factors; D000375:Aging / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D002448:Cell Adhesion; D002478:Cells, Cultured; D002633:Chemotaxis; D004002:Clodronic Acid / Q000494:pharmacology; D004195:Disease Models, Animal; D005340:Fibrinogen / Q000378:metabolism*; D005786:Gene Expression Regulation; D006965:Hyperplasia; D018836:Inflammation Mediators / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D058426:Neointima; D019899:Paracrine Communication / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction; D013997:Time Factors; D057772:Vascular System Injuries / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control
chemical_list: D018836:Inflammation Mediators; D020382:Interleukin-18; D004002:Clodronic Acid; D005340:Fibrinogen
keywords: aging; inflammation; neointima; vascular injury; vascular smooth muscle cells