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

Abstract

We previously developed a tissue-engineered vascular graft (TEVG) made by seeding autologous cells onto a biodegradable tubular scaffold, in an attempt to create a living vascular graft with growth potential for use in children undergoing congenital heart surgery. Results of our clinical trial showed that the TEVG possesses growth capacity but that its widespread clinical use is not yet advisable due to the high incidence of TEVG stenosis. In animal models, TEVG stenosis is caused by increased monocytic 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 ( Ccr2), splenectomized, and spleen graft recipient mice. We found that bone marrow-derived Ly6C monocytes released from sequestration by the spleen are the source of mononuclear cells infiltrating the TEVG during the acute phase of neovessel formation. Furthermore, short-term administration of losartan (0.6 g/L, 2 wk), an angiotensin II type 1 receptor antagonist, significantly reduced the macrophage populations (Ly6C/F480) in the 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 for pharmacologic treatment with losartan as a strategy to modulate monocyte infiltration into the grafts and thus prevent TEVG stenosis.-Ruiz-Rosado, J. D. D., Lee, Y.-U., Mahler, N., Yi, T., Robledo-Avila, F., Martinez-Saucedo, D., Lee, A. Y., Shoji, T., Heuer, E., Yates, A. R., Pober, J. S., Shinoka, T., Partida-Sanchez, S., Breuer, C. K. Angiotensin II receptor I blockade prevents stenosis of tissue engineered vascular grafts.

Progressive Reinvention or Destination Lost? Half a Century of Cardiovascular Tissue Engineering

“…Experimental work suggested that higher seeding densities may mitigate graft stenosis ( 160 , 161 ). Alternatively, pharmacological interventions were tested emulating the previously tried ACE inhibitor therapy ( 165 ) with modern angiotensin II receptor blockade ( 166 ). Eventually, single stage seeding of degradable scaffolds was carried over to heart valves and tested in acute ( 167 ) and semi-acute ( 168 ) sheep implants.…”

Immunomodulation Strategies for the Successful Regeneration of a Tissue‐Engineered Vascular Graft

“…Compared to the unseeded control, the BM‐MNC seeded grafts showed elevated patency rates, concentric layers of aligned SMCs, a confluent EC monolayer, and collagen‐rich ECM. [ 68,69 ] These observations correlate with less platelet adhesion, [ 101 ] less platelet activation (as measured in terms of platelet‐derived ATP), less macrophage infiltration, and a higher ratio of M2 macrophages in the seeded graft. [ 102 ] The BM‐MNCs were found to secrete MCP‐1, which enhanced monocyte recruitment during the first week after implantation.…”

Failure Analysis of TEVG’s I: Overcoming the Initial Stages of Blood Material Interaction and Stabilization of the Immune Response

“…(C) an incomplete endothelium and a mismatch in the mechanical properties with a flow disturbance will induce the activation of a synthetic phenotype in SMCs, that will overproliferate and decrease the vessel lumen [17]. (D) The lack in the mechanical properties of the TEVG required for specific hemodynamic conditions or a faster biodegradability rate than the vascular wall regeneration is expected to cause aneurysms [18,19]. (E) A slower biodegradability rate than the vascular wall regeneration is likely to cause a higher influx of pro-inflammatory cells, that might lead to a dysregulated balance between the synthesis and the degradation of the novo extracellular matrix, and if there is a chronic inflammatory stimulus, atherogenesis can occur with calcium and phosphate deposition in the disorganized tissue [20].…”