MicroRNA-155 Promotes the Directional Migration of Resident Smooth Muscle Progenitor Cells by Regulating Monocyte Chemoattractant Protein 1 in Transplant Arteriosclerosis

Abstract

Objective— Smooth muscle–like cells are major cell components of transplant arteriosclerosis lesions. This study investigated the origin of the smooth muscle–like cells, the mechanisms responsible for their accumulation in the neointima, and the factors that drive these processes. Approach and Results— A murine aortic transplantation model was established by transplanting miR-155 −/− bone marrow cells into miR-155 +/+ mice. MicroRNA-155 was found to play a functional role in the transplant arteriosclerosis. Moreover, we found that the nonbone marrow–derived progenitor cells with markers of both early differentiated smooth muscles and stem cells in the allograft adventitia were smooth muscle progenitor cells. Purified smooth muscle progenitor cells expressed a mature smooth muscle cell marker when induced by platelet-derived growth factor-BB in vitro. In vivo, these cells could migrate into the intima from the adventitia and could contribute to the neointimal hyperplasia. The loss of microRNA-155 in bone marrow–derived cells decreased the concentration gradient of monocyte chemoattractant protein 1 between the intima and the adventitia of the allografts, which reduced the migration of smooth muscle progenitor cells from the adventitia into the neointima. Conclusions— This study demonstrated that microRNA-155 promoted the directional migration of smooth muscle progenitor cells from the adventitia by regulating the monocyte chemoattractant protein 1 concentration gradient, which aggravated transplant arteriosclerosis.

TNF-α elicits phenotypic and functional alterations of vascular smooth muscle cells by miR-155-5p–dependent down-regulation of cGMP-dependent kinase 1

“…However, miR-155-5p appears to play a conflicting role, either as pro-or anti-atherogenic, in the pathogenesis of atherosclerosis (44). Recently, advanced studies have clearly demonstrated that this miRNA is pro-atherogenic in a high fat-induced atherosclerosis model and a vascular injury model using miR-155 Ϫ/Ϫ mice (45,46), although they did not identify the target genes. Although miR-155-15 can target multiple mRNAs, we propose that it may play an important role in VSMC dysfunction by suppressing PKG1 expression in inflammatory conditions.…”

Vascular Smooth Muscle Cells

“…13-16, 29-31, 68-70 An understanding of these phenotype transitions will most likely ultimately lead back to control of the SMC CArG box by myocardin and SRF together with the constellation of corepressors and coactivators that have been described to interact with this SMC differentiation platform. 32,71,72 Whether these phenotype transitions to macrophage-like, or osteoblast-like cell types are reversible in vivo , and what role resident SMC progenitor cells play in the homeostasis of the artery wall 73-77 are among the important questions going forward.…”

MicroRNA-155 promotes neointimal hyperplasia through smooth muscle-like cell-derived RANTES in arteriovenous fistulas

“…Smooth muscle-like cells (SMLCs) from the neointima of the outflow vein were isolated 3 weeks after AVF placement as previously described. 23 Briefly, the neointima was separated from the outflow vein under a light microscope and was digested in Dulbecco modified Eagle medium (DMEM) containing collagenase II (1 mg/mL; Worthington, Lakewood, NJ) at 37 C for 1 hour. The cells were then cultured in DMEM medium containing 10% fetal bovine serum and were used during passages three to seven.…”