Shear stress regulates connective tissue growth factor (CTGF) in vein graft remodeling

Introduction: Shear stress stands as a potent modulator of vascular remodeling with reduced shear leading to enhanced intimal hyperplasia within vein grafts. This shear-regulated intimal growth results from changes in cell proliferation and MMP-2 activation, however the mediators through which alterations in shear lead to remote changes in the developing neointima have not been well characterized. CTGF, acting as a downstream effecter of TGF-β, has a pivotal role in the regulation of matrix reorganization and cell homeostasis during pathologic stromal scar formation. We hypothesize CTGF to have a significant role the accelerated intimal growth seen in reduced shear conditions. Methods: Following bilateral carotid, vein graft placement within the rabbit neck (n = 9), partial distal branch ligation was performed on the right to create a flow differential between the grafts. Grafts were harvested at 28 days to evaluate morphology and CTGF gene and protein expression, using PCR (Taqman) and ELISA techniques. Immunohistochemistry was used to localize CTGF within the wall. Results: Unilateral ligation led to a significant disparity in wall shear (5.6 ± 1.1 vs. 1.2 ± 0.4 dynes/cm2, p = 0.01). Grafts demonstrated a marked difference in remodeling, with decreased intimal area under high shear conditions (21 ± 4 vs. 89 ± 8 mm2, p = 0.001). A significant interaction between CTGF and the imposed hemodynamic environment was observed, with elevations in shear stress leading to marked up-regulation of CTGF. Immunohistochemistry for CTGF revealed localization of protein almost exclusively to the endothelium. Conclusions: Elevated shear stress leads to an increase in endothelial CTGF production during early graft remodeling, suggesting CTGF to be an important mediator of intimal hyperplasia. Intervention in CTGF signaling may offer a therapeutic strategy to reduce vein graft failure. Download high-res image (131KB) Download full-size image