Abstract 18618: Endothelial to Mesenchymal Transition Contributes to Atherosclerotic Plaque Formation and Correlates With Plaque Instability
Introduction: Endothelial to mesenchymal transition (EndMT) contributes to several adult cardiovascular diseases. Mesenchymal cells including fibroblasts regulate inflammation, extracellular matrix and plaque structural integrity, but their origin in atherosclerosis is unknown.
Methods and Results: Tamoxifen inducible endothelial cell (EC) lineage tracking mice (end.SclCreERT;R26RYfp;ApoE-/-) fed high fat diet (HFD) from 6w age were used to quantify EndMT (YFP+ mesenchymal cells). By fluorescence labeling after 8w HFD, 32.5±8.5% of intimal plaque fibroblasts were EC-derived, while in advanced plaques (30w HFD) 45.5±23.3% of fibroblasts were EC-derived. Flow cytometry confirmed 36.2±3.6% of EC-derived cells were fibroblasts (18w HFD). Plaques showed marked oxidative stress, hypoxia and YFP+ cell apoptosis, most notably in advanced plaques (P<0.0001, <0.0001, <0.05 respectively). In human plaques, 4-10% and 10-18% of intimal cells co-expressed EC and fibroblast markers in type V and advanced VI plaques respectively. We identified increased EndMT (FAP+vWF+ cells) in ruptured vs. non-ruptured plaques (A), and an inverse relationship between fibrous cap thickness and extent of EndMT (FAP+vWF+ cells) (B). We confirmed oxidative stress promotes EndMT using hydrogen peroxide (H2O2). Hierarchical gene expression clustering showed human umbilical vein EC s (HUVECs) treated with TGFβ cluster with unstimulated cells, while HUVECs treated with TGFβ+H2O2 cluster separately and resemble native fibroblasts (C). HUVECs driven to undergo EndMT show increased MMP activity and MMP1, 9, and 10 expression than native fibroblasts (D), suggesting a link between EndMT, collagen-matrix balance and plaque vulnerability.
Conclusion: EndMT is a major factor in atherosclerosis progression. EndMT, abundant in advanced plaques, alters collagen-MMP balance and holds therapeutic potential.
Author Disclosures: L. Lecce: None. S.M. Evrard: None. K.C. Michelis: None. A. Nomura-Kitabayashi: None. G. Pandey: None. K. Purushothaman: None. V. d’Escamard: None. L.R. Jennifer: None. L. Hadri: None. K. Fujitani: None. P.R. Moreno: None. L. Benard: None. P. Rimmele: None. A. Cohain: None. B. Mecham: None. G.J. Randolph: None. E.G. Nabel: None. R. Hajjar: None. V. Fuster: None. M. Boehm: None. J.C. Kovacic: None.
- © 2016 by American Heart Association, Inc.