Increased Flow and Shear Stress Enhance In Vivo Transforming Growth Factor-β1 After Experimental Arterial Injury

Abstract

Abstract —We have previously demonstrated that high-flow (HF) conditions inhibit experimental intimal hyperplasia. We hypothesized that such flow conditions may alter transforming growth factor-β1 (TGF-β1) after mural injury. The right common carotid artery (CCA) was balloon-injured in 54 New Zealand White male rabbits. Flow was thereafter preserved (normal flow [NF]), reduced by partial outflow occlusion (low flow [LF]), or increased by ligation of the left CCA (HF). Four sham-operated animals served as uninjured controls. Mean blood flow and pressure in the right CCA were measured before and after flow modulation and before euthanasia (3, 7, and 14 days). TGF-β1 mRNA and protein levels in the right CCA were determined by Northern and ELISA analyses at each time point. At 7 and 14 days, intimal hyperplasia was quantified, and the transmural localization of TGF-β1 was determined by immunohistochemical analysis. Mean flow was reduced from 22±1 to 10±3 mL/min in the LF group and increased to 34±2 mL/min in the HF group ( P <0.001). Blood pressure was not different among the flow groups for all time points. Wall shear stress was markedly decreased in the LF group to 14±4 dyne/cm 2 and increased in the HF group to 63±6 dyne/cm 2 at 7 days compared with values in uninjured controls (39±2 dyne/cm 2 , P <0.001) and the NF group (44±7 dyne/cm 2 , P <0.001). At 14 days, wall shear stress was similar among the flow groups. The intima-to-media ratio was 5- and 2-fold greater in the LF group than in the HF and NF groups at 14 days. mRNA levels for TGF-β1 and its active ligand were increased in the HF group by at least 2- and 3-fold, respectively, at 3 and 7 days compared with levels in uninjured controls and the LF group ( P <0.05) but were not different among the flow groups at 14 days. TGF-β1 preferentially localized in the abluminal vascular smooth muscle cells of the HF arterial segments. Flow- and shear-mediated release of TGF-β1 may therefore play a role in abrogating the proliferative and migratory response of vascular smooth muscle cells in the early stages after mural injury.