Monckeberg's arteriosclerosis is a form of vessel hardening in which calcium deposits are found in the medial layer of elastic and muscular arteries, specifically on elastic fibers, leading to arterial stiffening and tearing. An independent risk factor for cardiovascular diseases in diabetic and chronic kidney-disease patients, it predisposes patients to cardiovascular mortality and lower extremity amputation. There are no treatments to reverse calcification. Elastin protein has a half-life of >60 years with almost no turnover. During aging and disease processes, elastic fibers degrade and are prone to calcification. We have developed unique nanoparticles that can be targeted to degraded elastic lamina in vasculature while sparing healthy arteries. This project is focused on removing mineral deposits by targeting chelating agent ethylene diamine tetra acetic acid (EDTA) to the degraded and calcified elastin in arteries. Then, nanoparticles loaded with pentagalloyl glucose (PGG) will be targeted to seal calcium-binding sites, inhibit enzymatic degradation, and restore lost elastin to improve vascular elasticity. Our strong published data show that such targeted EDTA chelation therapy, based on albumin nanoparticles, reverses experimentally created vascular calcification and avoids possible side effects of systemic chelation therapy. We would like to take this approach forward in a clinically relevant animal model of chronic kidney failure caused by adenine and high phosphorus diet.
In Specific Aim 1, we will test the hypothesis that reversal of elastin-specific vascular calcification is possible when targeted nanoparticles deliver a chelating agent, EDTA, to the site of vascular calcification in a rat model of adenine-induced uremia that causes vascular calcification. We will also determine whether calcification returns after termination of EDTA therapy by monitoring animals for extended periods and whether such therapy has any adverse effect on bone density and organ health.
In Specific Aim 2, we will test the hypothesis that dual therapy of targeted NPs carrying EDTA (to remove mineralization) followed NPs carrying PGG (to block calcium binding sites) will prevent return of vascular calcification and improve vascular function irrespective of CKD disease in a rat model of adenine-induced uremia. Such PGG therapy will also prevent further enzymatic degradation of elastin and reverse chondro/osteogenic phenotypic change of vascular smooth muscle cells.
In Specific Aim 3, using genetically altered mice, we will test the hypothesis that permanent reversal of calcification will lead to vascular homeostasis through reversing transdifferentiation of VSMC-osteoblast-like cell transition or by repopulation of media with new VSMCs from either pericytes, endothelial to mesenchymal transition (EndoMT), or hematopoietic stem cell (HSC) migration. With successful completion of these studies, we will, for the first time, have developed a targeted therapy approach to remove vascular calcification. This research, if successful, will lead to new therapies to improve vascular health in CKD and diabetic patients with vascular calcification.
Vascular calcification during aging and in diseases like diabetes and chronic kidney disease (CKD) causes arterial stiffening and increase in blood pressure. It is a significant unresolved health problem that is recognized as a strong predictor of cardiovascular events and mortality. We will test whether targeted nanoparticle-based intravenous delivery of chelating agent ethylene diamine tetraacetic acid (EDTA) will remove mineral deposits in arteries in rodent models of CKD. We will further test if dual nanoparticle-based therapy of EDTA (to remove mineralization) and pentagalloyl glucose (to prevent further mineral binding) improves vascular elasticity. Detailed cell tracing studies will complement the therapy approach to understand the mechanisms of calcification and the effect of vascular smooth muscle cell transformation to osteoblast like cells during vascular calcification. Such methods, if successfully translated to humans, could provide treatment options and thus considerably improve quality of life for millions of patients.
