Origin of neointimal endothelium and α-actin–positive smooth muscle cells in transplant arteriosclerosis
Jan-Luuk Hillebrands, … , Paul Nieuwenhuis, Jan Rozing
Jan-Luuk Hillebrands, … , Paul Nieuwenhuis, Jan Rozing
Published June 1, 2001
Citation Information: J Clin Invest. 2001;107(11):1411-1422. https://doi.org/10.1172/JCI10233.
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Origin of neointimal endothelium and α-actin–positive smooth muscle cells in transplant arteriosclerosis

Abstract

The development of transplant arteriosclerosis (TA) is today’s most important problem in clinical organ transplantation. Histologically, TA is characterized by perivascular inflammation and progressive intimal thickening. Current thought on this process of vascular remodeling assumes that neointimal vascular smooth muscle (VSM) cells and endothelium in TA are graft-derived, holding that medial VSM cells proliferate and migrate into the subendothelial space in response to signals from inflammatory cells and damaged graft endothelium. Using MHC class I haplotype-specific immunohistochemical staining and single-cell PCR analyses, we show that the neointimal α-actin–positive VSM cells in rat aortic or cardiac allografts are of recipient and not of donor origin. In aortic but not in cardiac allografts, recipient-derived endothelial cells (ECs) replaced donor endothelium. Cyclosporine treatment prevents neointima formation and preserves the vascular media in aortic allografts. Recipient-derived ECs do not replace graft endothelium after cyclosporine treatment. We propose that, although it progresses beyond the needs of functional repair, TA reflects the activity of a normal healing process that restores vascular wall function following allograft-induced immunological injury.

Authors

Jan-Luuk Hillebrands, Flip A. Klatter, Bart M.H. van den Hurk, Eliane R. Popa, Paul Nieuwenhuis, Jan Rozing

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Neointimal ECs in aortic allografts are of recipient origin. Immunohisto...
Neointimal ECs in aortic allografts are of recipient origin. Immunohistochemical staining using MHC class I haplotype-specific mAb’s was performed to determine the origin (donor vs. recipient) of neointimal ECs after allogeneic aorta transplantation. PVG allografts transplanted in AO recipients showed severe TA. (a) MHC class I expression on ECs (OX18-positive). Note the absence of VSM cells in the media (m). Donor endothelium had disappeared (OX27-negative) (b) and had been replaced by recipient-derived ECs (U9F4-positive) (c). Lew allografts transplanted into BN recipient rats also showed severe TA. (d) MHC class I expression on ECs (OX18-positive). (e) Donor endothelium had been replaced by recipient-derived ECs (OX27-positive). After CsA treatment, no neointima formation was observed 1 month after transplantation. (f) ECs covering the internal elastic lamina expressed MHC class I antigens (OX18-positive). However, ECs were OX27 (recipient class I)–negative (g), indicating that after CsA treatment EC replacement does not occur. Arrowheads indicate positively stained ECs. Original magnification: ×400.