Endothelial dysfunction drives atherosclerotic plaque macrophage-dependent abdominal aortic aneurysm formation. Journal Articles uri icon

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abstract

  • 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.

authors

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

publication date

  • May 2025