Mature Vascular Smooth Muscle Cells, but Not Endothelial Cells, Serve as the Major Cellular Source of Intimal Hyperplasia in Vein Grafts

Abstract

Objective: Neointima formation is a primary cause of intermediate to late vein graft (VG) failure. However, the precise source of neointima cells in VGs remains unclear. Approach and Results: Herein we clarify the relative contributions of mature vascular smooth muscle cells (SMCs) and endothelial cells (ECs) to neointima formation in a mouse model of VG remodeling via the genetic-inducible fate mapping approaches. Regardless of the magnitude of neointima formation, the recipient arterial and the donor venous SMCs contributed ≈55% of the neointima cells at the anastomotic regions, whereas only donor venous SMCs donated ≈68% of the neointima cells at the middle bodies. A small portion of the SMC-derived cells became non-SMC cells, most likely vascular stem cells, and constituted 2% to 11% of the cells in each major layer of VGs. In addition, the recipient arterial ECs were the major cellular source of re-endothelialization but did not contribute to neointima formation. The donor venous ECs donated ≈17% neointima cells in the VGs with mild neointima formation and conditional media from ECs after endothelial-to-mesenchymal transition suppressed vascular SMC dedifferentiation. Conclusions: The recipient arterial and donor venous mature SMCs dominate but contribute distinctly to intimal hyperplasia at the anastomosis and the middle body regions of VGs. The recipient arterial ECs are the major cellular source of re-endothelialization but do not donate neointima formation in VGs. Only the donor venous ECs undergo endothelial-to-mesenchymal transition. Endothelial-to-mesenchymal transition is marginal for generating neointima cells but is likely required for controlling the quality of VG remodeling.

miRNA-126-3p carried by human umbilical cord mesenchymal stem cell enhances endothelial function through exosome-mediated mechanisms in vitro and attenuates vein graft neointimal formation in vivo

“…The vein graft model and hucMSC transplantation were performed by using our previously described methods [ 18 , 19 ]. Briefly, rats were randomly divided into 5 groups as follows: [ 1 ] sham group, [ 2 ] vein graft group, [ 3 ] vein graft+hucMSCs group (hucMSCs group), [ 4 ] vein graft+GFP-hucMSCs group (GFP-hucMSCs group), and [ 5 ] vein graft+miRNA-126-3p-hucMSCs group (miRNA-126-3p-hucMSCs group). End-to-end anastomosis using “cuff technology” was performed to establish arteriovenous bypass grafting model in the vein graft group and all three hucMSC transplantation groups.…”

“…The initiation and trigger of vein graft intimal hyperplasia is the damage and loss of endothelial integrity caused by operative injury, hemodynamic changes, and inflammation [ 4 ]. The main pathology of vein graft restenosis highlights the abnormal proliferation of subendothelial smooth muscle cells and increased deposition of extracellular matrix [ 5 ]. Thus, repairing the damaged endothelium and improving endothelial function to accelerate reendothelialization is crucially important to prevent the initiation and development of vein graft intimal thickening and failure.…”

Circular RNA UVRAG Mediated by Alternative Splicing Factor NOVA1 Regulates Adhesion and Migration of Vascular Smooth Muscle Cells

“…Vascular smooth muscle cells (VSMCs) proliferate and migrate to the intima, leading to intimal hyperplasia, and are an important pathological basis for vascular restenosis. Wu et al indicated that VSMCs derived from the donor vein contributed 68% of neointimal cells in the middle segment of the graft vein [ 5 ]. Using gene therapy strategies to find specific targets that inhibit VSMCs migration to the intima may be an effective means to prevent vein graft failure.…”

miRNA-126-3p Carried by Human Umbilical Cord Mesenchymal Stem Cell Enhances Endothelial Function through Exosome-mediated Mechanisms in Vitro and Attenuates Vein Grafts Neointimal Formation in Vivo

“…The initiation and trigger of vein graft intimal hyperplasia is the damage and loss of endothelial integrity caused by operative injury, hemodynamic changes and in ammation 4 . The main pathology of vein graft restenosis highlights the abnormal proliferation of subendothelial smooth muscle cells and increased deposition of extracellular matrix 5 . Thus, repairing the damaged endothelium and improving endothelial function to accelerate reendothelialization is crucially important to prevent the initiation and development of vein graft intimal thickening and failure.…”