Role of the mTOR Signalling Pathway in Experimental Rabbit Vein Grafts

Abstract

Background: Coronary artery bypass grafting is employed for the treatment of multiple-vessel lesions. Studies have shown that continued maladaptive remodelling expedites atherosclerosis and that excessive remodelling leads to graft restenosis. However, few studies have focussed on mechanistic target of rapamycin (mTOR) signalling involved during remodelling of transplanted veins.

Methods: Rabbits were randomly allocated to groups undergoing vein-graft restenosis or sham surgery. At 1, 3, 7, 14, 28 and 90 days after surgery, we removed bypassed grafts and placed them in groups named T₁, T₂, T₃, T₄, T₅ and T₆, respectively. Group T₀ denoted the control group. Analysis included vessel thickness, electron microscope data, TUNEL staining, and expression of the proliferation-associated gene proliferating cell nuclear antigen (PCNA). We chose specific time-points of gene expression, and then observed changes in the mTOR signalling.

Results: The early stage of vein grafting (one to three days after surgery) led to apoptosis and degradation of the extracellular matrix. Seven days after surgery, cells began to proliferate. RICTOR expression in mTOR complex 2 (mTORC2) and that of its downstream substrate protein kinase C was enhanced in the early stage (T₁ and T₃), and was higher in T₁. mTORC1's upstream gene regulation decreased in T₁ and increased in T₃. Its downstream genes eIF4b and 4E-BP showed similar changes. Expression of eIF4e and eIF4b increased, and led to an increase in protein composition.

Conclusions: After transplantation, mTORC1 function and its upstream and downstream genes were inhibited on the first day after grafting, but mTORC2 function was enhanced. One week after surgery, mTORC2 was still overexpressed when mTORC1 function had recovered and became enhanced. Hence, mTORC2 plays a major role in arterialisation of veins.

Keywords: Vascular remodelling; Vein arterialisation; Vein graft restenosis; mTORC1/2.