Partial endothelial-to-mesenchymal transition mediated by HIF-induced CD45 in neointima formation upon carotid artery ligation


 
 
 Endothelial-to-mesenchymal transition (EndMT) is a fundamental process in vascular remodeling. However, the precise regulatory mechanism of vascular remodeling during neointima formation and source of neointima cells are not entirely understood.
 
 
 
 To investigate the origin of neointima cells and their relevance to vascular wall remodeling, we used an EC-specific lineage tracing system (VE-Cadherin (Cdh5)-BAC-CreERT2 mice) and carotid artery ligation model, and showed evidence that resident endothelial cells (ECs) transdifferentiate into neointima cells with expression of CD45. During the early stages of neointima formation, ECs transiently expressed CD45, a hematopoietic marker, accompanied by a host of EndMT markers, and CD31 and αSMA were prominently expressed in developing neointima. In vitro, CD45-positive EndMT was induced by stabilization of HIF1α with cobalt chloride or with a VHL inhibitor in human primary ECs, which mimicked the hypoxic condition of the ligated artery, and promoted the formation of an integrin α11-SHARPIN complex. Notably, a CD45 phosphatase inhibitor disrupted this complex, thereby destabilizing cell-cell junctions. Deletion of Hif1α in ECs suppressed expression of CD45 and EndMT markers, and ameliorated neointima formation.
 
 
 
 These results suggest that the HIF-induced CD45 expression is normally required for the retention of an EC fate and cell-cell junctions, CD45-positive EndMT (termed as “partial EndMT”) contributes to neointima formation and vascular wall remodeling.
 
 
 
 Our study identifies ECs as an origin of neointima, which is generated through partial EndMT and provides new evidence to the long-debated origin of neointimal cells after vascular injury. The ectopic CD45 expression in ECs is involved in the maintenance of endothelial cell-cell junction during EndMT process. Our data suggests a potential therapeutic strategy targeting the EndMT process to control neointima formation.
