Hemodynamic Influence on Smooth Muscle Cell Kinetics and Phenotype During Early Vein Graft Adaptation

Pathologic vascular adaptation following local injury is the primary driver for accelerated intimal hyper- plasia and an occlusive phenotype. Smooth muscle cell (SMC) proliferation within the wall, and migration into the developing intima, is a major component of this remodeling response. The primary objective in the current study was to investigate the effect of the local biomechanical forces on early vein graft adaptation, specifically focusing on the spatial and temporal response of SMC proliferation and conversion from a contractile to synthetic architecture. Taking advantage of the differential adaptation that occurs during exposure to divergent flow environments, vein grafts were implanted in rabbits to create two distinct flow environments and harvested at times ranging from 2 h to 28 days. Using an algorithm for the virtual reconstruction of unfixed, histologic specimens, immunohistochemical tracking of DNA synthesis, and high-throughput transcriptional analysis, the spatial and temporal changes in graft morphol- ogy, cell proliferation, and SMC phenotype were catalogued. Notable findings include a burst of cell proliferation at 7 days post-implantation, which was significantly augmented by exposure to a reduced flow environment. Compared to the adjacent media, proliferation rates were 3-fold greater in the intima, and a specific spatial distribution of these prolifer- ating cells was identified, with a major peak in the sub- endothelial region and a second peak centering on the internal elastic lamina. Genomic markers of a contractile SMC phenotype were reduced as early as 2 h post-implan- tation and reached a nadir at 7 days. Network analysis of upstream regulatory pathways identified GATA6 and KLF5 as important transcription factors that regulate this shift in SMC phenotype.