Endoluminal smooth muscle cell seeding limits intimal hyperplasia

Abstract

Purpose: Intimal hyperplasia is one of the main responses of the vascular wall to injury. In the current study, we tested the hypothesis that endoluminal seeding of host syngeneic vascular cells could limit intimal hyperplasia induced by either mechanical deendothelialization or chronic allograft rejection in rat aorta. Methods: An experimental model of in situ seeding of syngeneic endothelial cells, smooth muscle cells (SMCs), and fibroblasts (FIBs) was used in mechanically deendothelialized and allografted aortas. In a preliminary study, the ability of the three cell types (n = 5 per group) to seed on the deendothelialized luminal surface of the aortic wall was evaluated after 2 days, with the use of fluorescent PKH as marker. In the first model, the abdominal aorta of Lewis rats was deendothelialized (n = 6) or deendothelialized and seeded with either SMCs (n = 6) or FIBs (n = 6) before flow was restored. In the allograft model, aortas were harvested from dark agouti rats and orthotopically grafted in Lewis receivers, directly (n = 6) or after deendothelialization. Deendothelialization was performed alone (n = 6) or associated with the seeding of similar host (Lewis) syngeneic SMCs (n = 6) or FIBs (n = 6). Results were evaluated at 2 months with histologic and morphometric methods. Results: SMCs and FIBs were able to adhere in situ to the deendothelialized aortic wall, whereas endothelial cells were not. In mechanically deendothelialized aortas, the seeding of syngeneic SMCs led to a significant reduction in intimal thickness compared with deendothelialized aortas or FIB-seeded aortas (26.9 ± 1.7 μm vs 55.5 ± 1.7 and 56.7 ± 1.7 μm, respectively), and a lower nuclear content (382.2 ± 35.7 μm2 vs 779.6 ± 65.9 and 529.6 ± 24.3 μm2, respectively) of neointima. After SMC seeding, intimal hyperplasia was richer in elastin, whereas after FIB seeding it was richer in collagen. In allografts, the seeding of syngeneic SMC led to a significant reduction in intimal thickness compared with control aortas, deendothelialized aortas, or FIB-seeded aortas (31.6 ± 1.1 μm vs 88.55 ± 2.8, 74.6 ± 2.9, and 85.7 ± 2.6 μm, respectively), and a reduced nuclear content of the neointima (444.9 ± 23.4 μm2 vs 1529.1 ± 116, 972.3 ± 50, and 645.2 ± 32.4 μm2, respectively). Differences observed in the extracellular matrix composition were equivalent to those observed in the mechanically deendothelialized model. Conclusions: Our results suggest that endoluminal seeding of syngeneic SMCs can be effective in reducing intimal hyperplasia both in a deendothelialization model and in arterial allografts. SMC and FIB endoluminal seeding led to a significatively different accumulation of extracellular matrix in the intima.