Targeting the Caveolae-Dependent Mechanism of Calcifying Extracellular Vesicle Formation

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PROJECT SUMMARY Vascular calcification is the most significant predictor of cardiovascular morbidity and is especially prevalent in individuals with chronic kidney disease. Widespread arterial mineral in these patients disrupts vascular function and increases afterload on the heart. No therapeutic strategies currently exist to prevent or treat vascular calcification. Development of therapeutics is hindered by an incomplete understanding of the mineral formation process. Calcific mineral formation in the vascular wall begins in extracellular vesicles (EVs) that promote interactions between calcium and phosphate ions. Published data show that calcifying EV formation requires the presence of caveolin-1, a structural component of plasma membrane invaginations known as caveolae. However, the mechanisms through which caveolae may initiate calcifying EV formation remain unclear. The proposed study seeks to track the formation of calcifying EVs back to caveolae within vascular smooth muscle cells. We hypothesize that caveolae trafficking into the cell initiates calcifying EV formation and confers mineralization potential to the nascent vesicles. We will study the role of epidermal growth factor receptor (EGFR) as a caveolin-1 interactor and potential novel mediator of calcifying EV formation. Aim 1 of the study explores the caveolae-dependent mechanisms through which EVs form and promote mineralization. We will analyze the evolution of calcifying EVs as mineralization progresses both in vivo and in vitro. Aim 2 will test the therapeutic potential of a clinically-relevant strategy to alter caveolae trafficking and calcifying EV formation to treat vascular calcification.