Due to both aging and the improved longevity of patients with cardiovascular disease, the US population is at an ever-increasing risk of developing peripheral arterial disease. Patients with peripheral arterial disease have stiffened arteries, and peripheral arterial disease doubles patients' cardiovascular mortality. Importantly arterial stiffening is thought to be reversible. While there are a number of factors that lead to atherosclerosis, we propose that there are unique molecular signatures in arteries of patients with PAD that are related to the stiffness and flow conditions of these arteries. We have identified an important role for thrombospondin-1 in these conditions. Here we will identify and test the modifiability of these pathways using in vitro and in vivo models of PAD conditions. In order to test translation of this work, human tissue will be used to test critical findings. Positive results will be useful in developing targeted strategies that disrupt these pathways and improve arterial health in our patients.
Peripheral arterial disease is a significant age-related disease that affects the stiffness and blood flow in affected arteries. The combination of these biomechanical conditions may predispose these arteries to progressive atherosclerosis and increase the severity of their disease, however the role of arterial stiffness in the progression of atherosclerosis is not known. Here we use advanced animal models to identify the role of arterial stiffness on the onset and progression of atherosclerosis in clinically relevant conditions and then test whether targeted inhibition of critical pathways can change the natural history of this pathologic arterial remodeling over time.
| Chadid, Tatiana; Morris, Andrew; Surowiec, Alexandra et al. (2018) Reversible secretome and signaling defects in diabetic mesenchymal stem cells from peripheral arterial disease patients. J Vasc Surg 68:137S-151S.e2 |
