title: Age-associated vascular inflammation promotes monocytosis during atherogenesis.
abstract: Aging leads to a proinflammatory state within the vasculature without disease, yet whether this inflammatory state occurs during atherogenesis remains unclear. Here, we examined how aging impacts atherosclerosis using Ldlr(-/-) mice, an established murine model of atherosclerosis. We found that aged atherosclerotic Ldlr(-/-) mice exhibited enhanced atherogenesis within the aorta. Aging also led to increased LDL levels, elevated blood pressure on a low-fat diet, and insulin resistance after a high-fat diet (HFD). On a HFD, aging increased a monocytosis in the peripheral blood and enhanced macrophage accumulation within the aorta. When we conducted bone marrow transplant experiments, we found that stromal factors contributed to age-enhanced atherosclerosis. To delineate these stromal factors, we determined that the vasculature exhibited an age-enhanced inflammatory response consisting of elevated production of CCL-2, osteopontin, and IL-6 during atherogenesis. In addition, in vitro cultures showed that aging enhanced the production of osteopontin by vascular smooth muscle cells. Functionally, aged atherosclerotic aortas displayed higher monocyte chemotaxis than young aortas. Hence, our study has revealed that aging induces metabolic dysfunction and enhances vascular inflammation to promote a peripheral monocytosis and macrophage accumulation within the atherosclerotic aorta.
authors.affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.|Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Du
authors.affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.|Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Wong
authors.affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.|Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.|Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.|Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mori
authors.affiliation: Section of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Noemi
authors.initials: N
authors.lastname: Rotllan
authors.affiliation: Section of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Price
authors.affiliation: Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, USA.
authors.forename: Anca D
authors.initials: AD
authors.lastname: Dobrian
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Hailong
authors.initials: H
authors.lastname: Meng
authors.affiliation: Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.|Department of Pathology, Yale School of Medicine, New Haven, CT, USA.|Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Kleinstein
authors.affiliation: Section of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandez-Hernando
authors.affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.|Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Goldstein
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D050197:Atherosclerosis / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D001808:Blood Vessels / Q000473:pathology*; D002452:Cell Count; D002633:Chemotaxis / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D059305:Diet, High-Fat; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D006410:Hematopoiesis / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007249:Inflammation / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000378:metabolism; D007964:Leukocytosis / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D011973:Receptors, LDL / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D017077:Culture Media, Conditioned; D018836:Inflammation Mediators; D015850:Interleukin-6; D011973:Receptors, LDL
keywords: aging; inflammation and atherosclerosis; monocyte; vasculature