Association of smooth muscle cell phenotypic modulation with extracellular matrix alterations during neointima formation in rabbit vein grafts

Purpose: To clarify the mechanisms of structural changes underlying vein graft stenosis that limits efficacy of bypass grafting operation, we examined the accumulation and distribution of various extracellular matrix (ECM) components during neointima formation in rabbit vein grafts and analyzed their correlation with proliferation and phenotypic modulation of smooth muscle cells (SMCs). Methods and Results: An autologous external jugular vein graft was transplanted into the carotid artery in 25 rabbits. After the restoration of blood flow, the graft was markedly dilated. Medial SMCs in the graft appeared to be injured, and they began to proliferate at day 4 and subsequently migrated and formed the neointima at day 7. The neointima observed at days 7 and 14 contained ECM components, including type I collagen, heparan sulfate, and chondroitin sulfate, and the intimal SMCs were phenotypically modulated from the differentiated-type (SM2-positive and SM embryonic-negative) to the dedifferentiated-type (SM2-negative and SM embryonic-positive) as determined with immunostainings for myosin heavy chain isoforms. The intimal SMC proliferation was maximal at 2 weeks and then decreased rapidly. However, the neointima continued to thicken thereafter throughout the 6-month period of the experiment, and ECM accumulation, such as type I collagen and decorin, a small dermatan sulfate proteoglycan, was a prominent feature observed in the hypocellular region of the deep intima from 2 months after the transplantation. The phenotype of the intimal SMCs gradually returned to the differentiated-type from the deep intima after 2 months, but a small number of the intimal SMCs remained in the dedifferentiated phenotype even at 6 months after the operation. Conclusion: The neointima in the vein graft was formed initially by means of migration and proliferation of the phenotypically modulated, dedifferentiated-type SMCs and continued to thicken by means of sustained ECM accumulation, including type I collagen and decorin, in association with the prolonged presence of the dedifferentiated-type SMCs. These chronologic features in cell kinetics and ECM accumulation may contribute to the frequent occurrence of graft wall thickening that occurs in the vein grafts.