Arteries adapt to their mechanical environment by undergoing remodeling of the structural scaffold via the action of matrix metalloproteinases (MMPs). Cell culture studies have shown that stretching vascular smooth muscle cells (VSMCs) positively correlates to the production of MMP-2 and -9. In tissue level studies, the expressions and activations of MMP-2 and -9 are generally higher in the outer media. However, homogeneous mechanical models of arteries predict lower stress and strain in the outer media, which appear inconsistent with experimental findings. The effects of heterogeneity may be important to our understanding of VSMC function since arteries exhibit structural heterogeneity across the wall. We hypothesized that local stresses, computed using a heterogeneous mechanical model of arteries, positively correlate to the levels of MMP-2 and -9 in situ. We developed a model of the arterial wall accounting for nonlinearity, residual strain, anisotropy, and structural heterogeneity. The distributions of elastin and collagen fibers in situ, measured in the media of porcine carotid arteries, showed significant nonuniformities. Anisotropy was represented by the direction of collagen fibers measured by the helical angle of VSMC nuclei. The points at which the collagen fibers became load bearing were computed, assuming a uniform fiber strain and orientation under physiological loading conditions, an assumption motivated by morphological measurements. The distributions of circumferential stresses, computed using both heterogeneous and homogeneous models, were correlated to the distributions of expressions and activations of MMP-2 and -9 in porcine common carotid arteries incubated in an ex vivo perfusion organ culture system under physiological conditions for . While strains computed using incompressibility were identical in both models, the heterogeneous model, unlike the homogeneous model, predicted higher circumferential stresses in the outer layer correlated to the expressions and activations of MMP-2 and -9. This implies that localized remodeling occurs in the areas of high stress and agrees with results from cell culture studies. The results support the role of mechanical stress in vascular remodeling and the importance of structural heterogeneity in understanding mechanobiological responses.