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Ruiz, Jessica

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Ruiz

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Jessica

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Ruiz, Jessica

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2015 - 20182

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Author's Publications: search.filters.isAuthorOfPublication.c7ab75e0-ad72-4232-969e-a1477530a94d

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    Nanoanalytical Analysis of Bisphosphonate-Induced Alterations of Microcalcifications Using a 3D Hydrogel Platform
    (2018-05-15) Ruiz, Jessica
    Vascular calcification predicts atherosclerotic plaque rupture and cardiovascular events. Retrospective studies of women taking bisphosphonates (BiPs), a proposed therapy for vascular calcification, showed that BiPs paradoxically increased cardiovascular morbidity in patients with prior acute events, but decreased morbidity in event-free patients. We recently demonstrated that calcifying extracellular vesicles (EVs) released by cells within atherosclerotic plaques aggregate and nucleate calcific mineral. We hypothesize that BiPs block EV aggregation and modify existing mineral growth, potentially altering microcalcification morphology and the resultant risk of plaque rupture. 3D collagen hydrogels incubated with calcifying EV mimicked fibrous cap calcification, serving as a platform to image mineral nucleation and test potential therapies for vascular calcification. This study visualized EV aggregation and formation of stress-inducing microcalcifications at single-EV resolution, via scanning electron microscopy (SEM) and atomic force microscopy (AFM). Finite element analysis (FEA) of a representative microcalcification formed in the 3D platform predicted a consequential 350% increase in fibrous cap tensile stress. Energy-dispersive x-ray spectroscopy (EDS) confirmed that EV aggregates contained calcium and phosphorous. BiP (ibandronate) treatment added on day 0 significantly decreased the size (21.5 μm2 vs. 14.2 μm2, p=0.012) and amount of EDS-detected calcium (4.32% by weight (wt%) vs. 2.36 wt%, p<0.001) and phosphorous (4.26 wt% vs. 1.94 wt%, p<0.001) comprising EV aggregates measured on day 8. However, an increase in mineral was measured when BiP was added at later time points. Mineral composition and morphology, measured with Fourier-transform infrared spectroscopy (FTIR), SEM and AFM, varied depending on the timing of BiP treatment, suggesting that BiP treatment altered microcalcification morphology and composition in a time-dependent manner. These findings support our hypothesis that BiP alter EV-driven calcification, which may help explain confounding clinical data. The study also confirmed that our 3D hydrogel is a viable platform to study EV-mediated mineral nucleation and evaluate potential therapies for cardiovascular calcification.
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    Genesis and growth of extracellular vesicle-derived microcalcification in atherosclerotic plaques
    (2015) Hutcheson, Joshua; Goettsch, Claudia; Bertazzo, Sergio; Maldonado, Natalia; Ruiz, Jessica; Goh, Wilson; Yabusaki, Katsumi; Faits, Tyler; Bouten, Carlijn; Franck, Gregory; Quillard, Thibaut; Libby, Peter; Aikawa, Masanori; Weinbaum, Sheldon; Aikawa, Elena
    Clinical evidence links arterial calcification and cardiovascular risk. Finite-element modelling of the stress distribution within atherosclerotic plaques has suggested that subcellular microcalcifications in the fibrous cap may promote material failure of the plaque, but that large calcifications can stabilize it. Yet the physicochemical mechanisms underlying such mineral formation and growth in atheromata remain unknown. Here, by using three-dimensional collagen hydrogels that mimic structural features of the atherosclerotic fibrous cap, and high-resolution microscopic and spectroscopic analyses of both the hydrogels and of calcified human plaques, we demonstrate that calcific mineral formation and maturation results from a series of events involving the aggregation of calcifying extracellular vesicles, and the formation of microcalcifications and ultimately large calcification zones. We also show that calcification morphology and the plaque’s collagen content – two determinants of atherosclerotic plaque stability - are interlinked.