期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1811725118
关键词
atherosclerosis; microcalcification; bisphosphonate; extracellular vesicles
资金
- NSF [1541959]
- American Heart Association [17SDG633670259]
- Consorzio Sistemi a Grande Interfase through the evFOUNDRY project, Horizon 2020-Future, and emerging technologies (H2020FETOPEN) [801367]
- Kowa Company
- NIH [R01 HL136431, R01 HL141917, R01 HL147095]
- Harvard Catalyst Big Ideas, Small Features: Advanced Microscopic and Nanoscale Technologies Pilot Award
The study demonstrates that bisphosphonates can alter EV-driven calcification process, affecting microcalcification morphology and risk of plaque rupture. The 3D hydrogel is a viable platform for studying EV-mediated mineral nucleation and evaluating potential therapies for cardiovascular calcification.
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 morbidity in patients with prior acute cardiovascular events but decreased mortality in event-free patients. Calcifying extracellular vesicles (EVs), released by cells within atherosclerotic plaques, aggregate and nucleate calcification. We hypothesized that BiPs block EV aggregation and modify existing mineral growth, potentially altering microcalcification morphology and the risk of plaque rupture. Three-dimensional (3D) collagen hydrogels incubated with calcifying EVs were used to mimic fibrous cap calcification in vitro, while an ApoE(-/-) mouse was used as a model of atherosclerosis in vivo. EV aggregation and formation of stress-inducing micro-calcifications was imaged via scanning electron microscopy (SEM) and atomic force microscopy (AFM). In both models, BiP (ibandronate) treatment resulted in time-dependent changes in microcalcification size and mineral morphology, dependent on whether BiP treatment was initiated before or after the expected onset of microcalcification formation. Following BiP treatment at any time, microcalcifications formed in vitro were predicted to have an associated threefold decrease in fibrous cap tensile stress compared to untreated controls, estimated using finite element analysis (FEA). These findings support our hypothesis that BiPs alter EV-driven calcification. 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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