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

Purpose: To clarify the mechanisms of structural changes underlying vein gr aft stenosis that limits efficacy of bypass grafting operation, we examined the accumulation and distribution of various extracellular matrix (ECM) co mponents during neointima formation in rabbit vein grafts and analyzed thei r correlation with proliferation and phenotypic modulation of smooth muscle cells (SMCs). Methods and Results: An autologous external jugular vein graft was transpla nted 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 migrate d and formed the neointima at day 7. The neointima observed at days 7 and 1 4 contained ECM components, including type I collagen, heparan sulfate, and chondroitin sulfate, and the intimal SMCs were phenotypically modulated fr om the differentiated-type (SM2-positive and SM embryonic-negative) to the dedifferentiated-type (SM2-negative and SM embryonic-positive) as determine d with immunostainings for myosin heavy chain isoforms. The intimal SMC pro liferation 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 transpla ntation. The phenotype of the intimal SMCs gradually returned to the differ entiated-type from the deep intima after 2 months, but a small number of th e 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 o f migration and proliferation of the phenotypically modulated, dedifferenti ated-type SMCs and continued to thicken by means of sustained ECM accumulat ion, including type I collagen and decorin, in association with the prolong ed presence of the dedifferentiated-type SMCs. These chronologic features i n cell kinetics and ECM accumulation may contribute to the frequent occurre nce of graft wall thickening that occurs in the vein grafts.