Effects of axial stretch and wall injury on intimal hyperplasia in arteries

Intimal hyperplasia (IH) remains the major cause of intermediate and long-term failure of vascular grafts and endovascular interventions. IH is an increase in the number of cells in the intima and the key events are migration and proliferation of smooth muscle cell with deposition of extracellular matrix. While the injury to endothelial cell is the main cause of IH, mechanical stresses such as circumferential stress or low wall shear stress also promote IH. Arteries are subjected to a significant longitudinal stress in addition to the shear stress and tensile stress from the blood flow and pressure. This axial stress may change dramatically due to aging, disease, or vascular surgery. However, the possible effect of axial stretch on IH has not been studied yet. . The overall objective of this study was to determine the effect of axial stretch on cell proliferation and IH in arteries. We hypothesized that the elevated axial stretch will promote the IH and cell proliferation in arteries. Porcine carotid arteries, intact or endothelial cell (EC) denudated, were maintained ex vivo at different stretch ratios (1.3, 1.5 and 1.8) and flow rates (16 or 160 ml/min) while remaining at physiologic pressure (100 ± 20 mmHg) for 7 or 14 days using an ex vivo organ culture system. The viability of the arteries was verified with norepinephrine, carbachol, and sodium nitroprusside stimulations and the cell proliferation was detected using bromodeoxyuridine labeling and immunostaining. Our results showed that increased axial stretch ratio alone did not significantly affect intimal thickness and cell proliferation in normal arteries in 7 day culture period. However, combined with EC denudation and low flow conditions, the axial stretch ratio affected IH (9.22 ± 2.57 vs. 5.56 ± 1.44, p<0.08 vs. relaxed, intact, normal flow) and showed significant effect on cell proliferation (For example, in intima, 74.96 ± 9.75 % vs. 3.34 ±3.88, p<0.0001 vs. relaxed, intact, normal flow). These results indicate the possible synergetic effect of axial stretch, low flow and EC denudation on cell proliferation and IH. The effect was more evident after 14 days. These results increase our understanding of the IH development after stenting and will be useful in developing new techniques to reduce and prevent IH and restenosis. Our results would help vascular surgeon in selecting the proper axial stretch level and vessel length for vascular grafting and in reconstructive vascular surgery.