Luminal shearing forces have been shown to impact both geometric remodeling and the development of intimal hyperplasia. Less well studied is the influence of intramural wall stresses on vessel growth and adaptation. Using a vein graft-fistula configuration to isolate the impact of circumferential wall stress, we identify the reorganization of adventitial myofibroblasts as the dominant histologic event that limits early outward remodeling of vein grafts in response to elevated wall stress. We hypothesize that increased production of TGF- and CTGF induces recruitment of myofibroblast, promotes adventitial reorganization, and limits early outward remodeling in response to increased intramural wall stress. Vein grafts with a distal arteriovenous fistula in the neck of rabbit were constructed, resulting in a 4-fold differential in circumferential wall stress. Using this model, we demonstrate: 1) elevated wall stress augments the production of TGF- and CTGF, 2) increased TGF- and CTGF expression is correlated with the enhanced differentiation from fibroblasts to myofibroblasts, as evidenced by the significant increase in the -actin positive cells in adventitia, and 3) the levels of TGF-, CTGF, and -actin are inversely correlated with the magnitude of outward remodeling of the graft wall. Increased wall stress following vein graft implantation appears to induce a TGF-/CTGF mediated recruitment of adventitial fibroblasts, and a conversion to a myofibroblast phenotype. While important in maintaining wall stability in the face of an increased mechanical load, this adventitial adaptation limits early outward remodeling of the vein conduit and may prove deleterious in maintaining long-term vein graft patency.