Prolonged Hyperoxygenation Treatment Improves Vein Graft Patency and Decreases Macrophage Content in Atherosclerotic Lesions in ApoE3Leiden Mice

• Published in: Cells (Basel, Switzerland) Vol. 9; no. 2; p. 336
• Main Authors: Parma, Laura, Peters, Hendrika A B, Baganha, Fabiana, Sluimer, Judith C, de Vries, Margreet R, Quax, Paul H A
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 01.02.2020; MDPI AG
• Subjects: Animals; Apolipoprotein E3 - metabolism; Apoptosis - drug effects; atherosclerosis; Atherosclerosis - complications; Atherosclerosis - pathology; Blood Vessel Prosthesis; Carbon Dioxide - pharmacology; DNA Damage; Hemorrhage - complications; Hemorrhage - pathology; Hemorrhage - physiopathology; hyperoxygenation; Hypoxia - complications; Hypoxia - pathology; Hypoxia - physiopathology; Inflammation - complications; Inflammation - pathology; macrophages; Macrophages - drug effects; Macrophages - metabolism; Male; Mice, Inbred C57BL; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Neovascularization, Pathologic - pathology; Oxygen - pharmacology; Plaque, Atherosclerotic - complications; Plaque, Atherosclerotic - pathology; Reactive Oxygen Species - metabolism; vascular biology; Vascular Patency - drug effects; vein graft disease; Veins - drug effects; Veins - physiopathology; atherosclerosis; vein graft disease; macrophages; vascular biology; hyperoxygenation
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells9020336

Unstable atherosclerotic plaques frequently show plaque angiogenesis which increases the chance of rupture and thrombus formation leading to infarctions. Hypoxia plays a role in angiogenesis and inflammation, two processes involved in the pathogenesis of atherosclerosis. We aim to study the effect of resolution of hypoxia using carbogen gas (95% O , 5% CO ) on the remodeling of vein graft accelerated atherosclerotic lesions in ApoE3*Leiden mice which harbor plaque angiogenesis. Single treatment resulted in a drastic decrease of intraplaque hypoxia, without affecting plaque composition. Daily treatment for three weeks resulted in 34.5% increase in vein graft patency and increased lumen size. However, after three weeks intraplaque hypoxia was comparable to the controls, as were the number of neovessels and the degree of intraplaque hemorrhage. To our surprise we found that three weeks of treatment triggered ROS accumulation and subsequent Hif1a induction, paralleled with a reduction in the macrophage content, pointing to an increase in lesion stability. Similar to what we observed in vivo, in vitro induction of ROS in bone marrow derived macrophages lead to increased Hif1a expression and extensive DNA damage and apoptosis. Our study demonstrates that carbogen treatment did improve vein graft patency and plaque stability and reduced intraplaque macrophage accumulation via ROS mediated DNA damage and apoptosis but failed to have long term effects on hypoxia and intraplaque angiogenesis.