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Angiotensin II receptor I blockade prevents stenosis of tissue engineered vascular grafts

Juan de Dios Ruiz-Rosado, Yong-Ung Lee, Nathan Mahler, Tai Yi, Frank Robledo-Avila, Diana Martinez-Saucedo, Avione Y Lee, Toshihiro Shoji, Eric Heuer, Andrew R Yates, Jordan S Pober, Toshiharu Shinoka, Santiago Partida-Sanchez, Christopher K Breuer
The FASEB Journal2018
We previously developed a tissue-engineered vascular graft (TEVG)made by seeding autologous cells onto a biodegradable tubular scaffold, in anattempt to create a living vascular graft with growthpotential foruse in children undergoing congenital heart surgery.Results of our clinical trial showed that the TEVGpossesses growth capacity but that its widespread clinical use is not yet advisable due to the high incidence of TEVG stenosis. In animalmodels, TEVGstenosis is caused by increasedmonocytic cell recruitment and its classic (“M1”) activation. Here, we report on the source and regulation of these monocytes. TEVGs were implanted in wild-type, CCR2 knockout (Ccr22/2), splenectomized, and spleen graft recipientmice.We found that bonemarrow–derivedLy6C+hi monocytes released from sequestration by the spleen are the source of mononuclear cells infiltrating the TEVG during theacutephase ofneovessel formation.Furthermore, short-termadministrationof losartan (0.6 g/L, 2wk), an angiotensin II type 1 receptor antagonist, significantly reduced themacrophage populations (Ly6C+/2/F480+)inthe scaffolds and improved long-term patency in TEVGs. Notably, the combined effect of bone marrow–derived mononuclear cell seeding with short-term losartan treatment completely prevented the development of TEVG stenosis.Our results provide support forpharmacologic treatmentwithlosartanas a strategy tomodulatemonocyte infiltration into the grafts and thus prevent TEVG stenosis.

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