Regulation of Cell Adhesion and De-Adhesion Proteins in Veins Perfused Under Arterial Conditions Ex-Vivo

Failure of veins employed as arterial bypass grafts via intimal hyperplasia (IH) often occurs within 5 years after implantation, requiring re-operation in 60% of all cases¹. IH is characterized by de-adhesion, followed by migration of medial and adventitial smooth muscle cells (SMCs) and myofibroblasts into the intima, where they demonstrate uncontrolled proliferation. It is thought that this process may be induced by the abrupt exposure of the veins to the dynamic mechanical environment of the arterial circulation². Veins are much thinner walled and more distensible than arteries. Therefore, the SMCs within the vein wall are exposed to significantly higher levels of stress and strain than they are accustomed². The tissue responds to this perceived injury by thickening, which is thought to be an attempt to return the stress and strain to venous levels. However, when this response is uncontrolled it can over-compensate, leading to stenosis instead of the desired thickening or “arterialization” of the vein segment. Cellular de-adhesion, which refers to a change from a state of stronger adherence to a state of weaker adherence, is involved in the earliest response and therefore was the focus of this study. While there are many important proteins involved in the regulation of cellular adhesion, we focus our attention here to matricellular proteins, which function as adaptors and modulators of cell-matrix interactions^3,4, and intracellular adhesion proteins, which have been shown to localize to cellular focal adhesion sites^5,6. Tenascin-C (TN-C), thrombospondin-1,2 (TSP), and secreted protein acidic and rich in cysteine (SPARC) are matricellular proteins that exhibit highly regulated expression during development and cellular injury⁷. Mitogen inducible gene 2 (Mig-2) and integrin linked kinase (ILK) are intracellular proteins involved in cellular shape modulation⁵ and integrin-mediated signal transduction⁸, respectively. It is well known that many intracellular and extracellular matrix proteins are regulated by mechanical stress^9,10. The purpose of this work was to explore the hypothesis that intact vein segments exposed to arterial hemodynamics will alter their expression of TN-C, TSP, SPARC, Mig-2 and ILK within 24 hours. This may induce a modulation of the level of cell adhesion, which could contribute to IH.