Glycosaminoglycans (GAGs) are increasingly thought to play important roles in arterial mechanics and mechanobiology. We recently suggested that these highly negatively charged molecules, well known for their important contributions to cartilage mechanics, can pressurize intralamellar units in elastic arteries via a localized swelling process and thereby impact both smooth muscle mechanosensing and structural integrity. In this paper, we report osmotic loading experiments on murine common carotid arteries that revealed different degrees and extents of transmural swelling. Overall geometry changed significantly with exposure to hypo-osmotic solutions, as expected, yet mean pressure-outer diameter behaviors remained largely the same. Histological analyses revealed further that the swelling was not always distributed uniformly despite being confined primarily to the media. This unexpected finding guided a theoretical study of effects of different distributions of swelling on the wall stress. Results suggested that intramural swelling can introduce highly localized changes in the wall mechanics that could induce differential mechanobiological responses across the wall. There is, therefore, a need to focus on local, not global, mechanics when examining issues such as swelling-induced mechanosensing.