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<p>Currently there is no effective pharmacotherapy to prevent the growth and rupture of abdominal aortic aneurysms. Using a mouse model that combines cigarette smoke exposure and hypercholesterolemia, we demonstrated that cigarette smoke exacerbated atherosclerosis, leading to elastin fragmentation, aneurysm formation, rupture and death. Arterial injury was driven by macrophages that accumulated within atherosclerotic plaques and exhibited tissue-degrading proteolytic activity in vivo (a process dependent on the endothelial cell-derived macrophage growth factor CSF-1). Single-nucleus RNA sequencing revealed that cigarette smoke-induced endothelial cell dysfunction promoted monocyte recruitment and inflammatory signaling and amplified vascular injury. Furthermore, single-cell transcriptomic analysis identified conserved macrophage responses across mouse and human abdominal aortic aneurysm, including TREM2<sup>+</sup> macrophages, which were key mediators of arterial damage. These findings established atherosclerotic plaque macrophages as critical drivers of aneurysm pathology and provide key insights into the mechanisms underlying aneurysm progression and rupture.</p>

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Endothelial dysfunction drives atherosclerotic plaque macrophage-dependent abdominal aortic aneurysm formation

  • 期刊论文

  • 发表日期：

    2025年4月22日

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  • Danya Thayaparan,
  • Takuo Emoto,
  • Aniqa B. Khan,
  • Rickvinder Besla,
  • Homaira Hamidzada,
  • Mahmoud El-Maklizi,
  • Tharini Sivasubramaniyam,
  • Shabana Vohra,
  • Ash Hagerman,
  • Sara Nejat,
  • Charlotte E. Needham-Robbins,
  • Tao Wang,
  • Moritz Lindquist,
  • Steven R. Botts,
  • Stephanie A. Schroer,
  • Masayuki Taniguchi,
  • Taishi Inoue,
  • Katsuhiro Yamanaka,
  • Haotian Cui,
  • Edouard Al-Chami,
  • Hangjun Zhang,
  • Marwan G. Althagafi,
  • Aja Michalski,
  • Joshua J. C. McGrath,
  • Steven P. Cass,
  • David Luong,
  • Yuya Suzuki,
  • Angela Li,
  • Amina Abow,
  • Rachel Heo,
  • Shaun Pacheco,
  • Emily Chen,
  • Felix Chiu,
  • John Byrne,
  • Tomoyuki Furuyashiki,
  • Mansoor Husain,
  • Peter Libby,
  • Kenji Okada,
  • Kathryn L. Howe,
  • Scott P. Heximer,
  • Tomoya Yamashita,
  • Bo Wang,
  • Barry B. Rubin,
  • Myron I. Cybulsky,
  • Joy Roy,
  • Jesse W. Williams,
  • Sarah Q. Crome,
  • Slava Epelman,
  • Ken-ichi Hirata,
  • Martin R. Stampfli,
  • Clinton S. Robbins

摘要

Currently there is no effective pharmacotherapy to prevent the growth and rupture of abdominal aortic aneurysms. Using a mouse model that combines cigarette smoke exposure and hypercholesterolemia, we demonstrated that cigarette smoke exacerbated atherosclerosis, leading to elastin fragmentation, aneurysm formation, rupture and death. Arterial injury was driven by macrophages that accumulated within atherosclerotic plaques and exhibited tissue-degrading proteolytic activity in vivo (a process dependent on the endothelial cell-derived macrophage growth factor CSF-1). Single-nucleus RNA sequencing revealed that cigarette smoke-induced endothelial cell dysfunction promoted monocyte recruitment and inflammatory signaling and amplified vascular injury. Furthermore, single-cell transcriptomic analysis identified conserved macrophage responses across mouse and human abdominal aortic aneurysm, including TREM2+ macrophages, which were key mediators of arterial damage. These findings established atherosclerotic plaque macrophages as critical drivers of aneurysm pathology and provide key insights into the mechanisms underlying aneurysm progression and rupture.