Impaired endothelial cell proliferative, migratory, and adhesive abilities are associated with the slow endothelialization of polycaprolactone vascular grafts implanted into a hypercholesterolemia rat model

Abstract

Most small diameter vascular grafts (inner diameter<6 mm) evaluation studies are performed in healthy animals that cannot represent the clinical situation. Herein, an hypercholesterolemia (HC) rat model with thickened intima and elevated expression of pro-inflammatory intercellular adhesion molecular-1 (ICAM-1) in the carotid branch is established. Electrospun polycaprolactone (PCL) vascular grafts (length: 1 cm; inner diameter: 2 mm) are implanted into the HC rat abdominal aortas in an end to end fashion and followed up to 43 days, showing a relative lower patency accompanied by significant neointima hyperplasia, abundant collagen deposition, and slower endothelialization than those implanted into healthy ones. Moreover, the proliferation, migration, and adhesion behavior of endothelial cells (ECs) isolated from the HC aortas are impaired as evaluated under both static and pulsatile flow conditions. DNA microarray studies of the HC aortic endothelium suggest genes involved in EC proliferation (Egr2), apoptosis (Zbtb16 and Mt1), and metabolism (Slc7a11 and Hamp) are down regulated. These results suggest the impaired proliferative, migratory, and adhesive abilities of ECs are associated with the bad performances of grafts in HC rat. Future pre-clinical evaluation of small diameter vascular grafts may concern more disease animal models with clinical complications. STATEMENT OF SIGNIFICANCE: During the development of small diameter vascular grafts (D<6 mm), young and healthy animal models from pigs, sheep, dogs, to rabbits and rats are preferred. However, it cannot represent the clinic situation, where most cardiovascular grafting procedures are performed in the elderly and age is the primary risk factor for disease development or death. Herein, the performance of electrospun polycaprolactone (PCL) vascular grafts implanted into hypercholesterolemia (HC) or healthy rats were evaluated. Results suggest the proliferative, migratory, and adhesive abilities of endothelial cells (ECs) are already impaired in HC rats, which contributes to the observed slower endothelialization of implanted PCL grafts. Future pre-clinical evaluation of small diameter vascular grafts may concern more disease animal models with clinical complications.

Keywords: Aortic endothelial cells; Endothelialization; Hypercholesterolemia rat; Polycaprolactone (PCL) graft.