Caveolin-1 regulates atherogenesis by attenuating low-density lipoprotein transcytosis and vascular inflammation independently of endothelial nitric oxide synthase activation

Cristina M. Ramirez, Xinbo Zhang, Chirosree Bandyopadhyay, Noemi Rotllan, Michael G. Sugiyama, Binod Aryal, Xinran Liu, Shun He, Jan R. Kraehling, Victoria Ulrich, Chin Sheng Lin, Heino Velazquez, Miguel A. Lasuncion, Guangxin Li, Yajaira Suarez, George Tellides, Filip K. Swirski, Warren L. Lee, Martin A. Schwartz, William C. SessaCarlos Fernandez-Hernando

Research output: Contribution to journalArticlepeer-review

93 Scopus citations


BACKGROUND: Atherosclerosis is driven by synergistic interactions between pathological, biomechanical, inflammatory, and lipid metabolic factors. Our previous studies demonstrated that absence of caveolin-1 (Cav1)/caveolae in hyperlipidemic mice strongly inhibits atherosclerosis, which was attributed to activation of endothelial nitric oxide (NO) synthase (eNOS) and increased production of NO and reduced inflammation and low-density lipoprotein trafficking. However, the contribution of eNOS activation and NO production in the atheroprotection of Cav1 and the exact mechanisms by which Cav1/caveolae control the pathogenesis of diet-induced atherosclerosis are still not clear. METHODS: Triple-knockout mouse lacking expression of eNOS, Cav1, and Ldlr were generated to explore the role of NO production in Cav1- dependent athero-protective function. The effects of Cav1 on lipid trafficking, extracellular matrix remodeling, and vascular inflammation were studied both in vitro and in vivo with a mouse model of diet-induced atherosclerosis. The expression of Cav1 and distribution of caveolae regulated by flow were analyzed by immunofluorescence staining and transmission electron microscopy. RESULTS: We found that absence of Cav1 significantly suppressed atherogenesis in Ldlr-/-eNOS-/- mice, demonstrating that atherosuppression is independent of increased NO production. Instead, we find that the absence of Cav1/caveolae inhibited low-density lipoprotein transport across the endothelium and proatherogenic fibronectin deposition and disturbed flow-mediated endothelial cell inflammation. Consistent with the idea that Cav1/caveolae may play a role in early flowdependent inflammatory priming, distinct patterns of Cav1 expression and caveolae distribution were observed in athero-prone and atheroresistant areas of the aortic arch even in wild-type mice. CONCLUSIONS: These findings support a role for Cav1/caveolae as a central regulator of atherosclerosis that links biomechanical, metabolic, and inflammatory pathways independently of endothelial eNOS activation and NO production.

Original languageEnglish
Pages (from-to)225-239
Number of pages15
Issue number3
StatePublished - 8 Jan 2019
Externally publishedYes


  • Atherosclerosis
  • Caveolae
  • Extracellular matrix
  • Fibronectins
  • Inflammation
  • Nitric oxide synthase type III
  • Transcytosis


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