Document Type



Doctor of Philosophy (PhD)


Biomedical Engineering

First Advisor's Name

Joshua D. Hutcheson

First Advisor's Committee Title

Committee chair

Second Advisor's Name

Jessica Ramella-Roman

Second Advisor's Committee Title

Committee member

Third Advisor's Name

Sharan Ramaswamy

Third Advisor's Committee Title

Committee member

Fourth Advisor's Name

Arvind Agarwal

Fourth Advisor's Committee Title

Committee member

Fifth Advisor's Name

Prem Chapagain

Fifth Advisor's Committee Title

Committee member


Cardiovascular calcification, Bisphosphonate, Vascular smooth muscle cell, Caveolin-1, Chronic kidney disease, Epidermal growth factor receptor, bone mineralization

Date of Defense



Cardiovascular diseases represent the global leading cause of morbidity and mortality. Cardiovascular calcification is the most significant predictor of cardiovascular events, but no therapeutic options exist to prevent or treat mineral formation in the vasculature. The presence of bone-like mineral increases cardiac work required to move blood through systemic circulation and can lead to mechanical stress in atherosclerotic plaques, promoting plaque rupture events that cause heart attacks. Clinical trials correlated bisphosphonates (BiPs), common anti-osteoporosis pharmaceuticals, with contradicting cardiovascular outcomes. Here, we demonstrated the importance of treatment timing in BiP-induced mineral disruption or promotion. We showed that BiPs can alter morphological features of calcifications within the atherosclerotic plaque of hyperlipidemic mice, which may affect plaque rupture risk.

Osteogenic differentiation of resident vascular smooth muscle cells (VSMCs) and release of calcifying extracellular vesicles (EVs) mediate cardiovascular calcification, which imitates bone mineralization by osteoblasts. Formation of calcifying EVs by VSMCs requires caveolin-1 (CAV1), a scaffolding membrane protein. Targeting cellular mechanisms that involve CAV1 may represent ideal strategies to develop therapeutics for cardiovascular calcification.

We studied the effect of inhibiting several upstream and downstream molecules that are involved in CAV1 activation and trafficking. Interestingly, we showed that altering CAV1 trafficking does not negatively impact physiological mineralization of osteoblasts. We concluded that despite shared mineralization characteristics, the mechanism(s) of bone and vascular calcification is/are distinct.

Furthermore, we demonstrated that epidermal growth factor receptor (EGFR) inhibition prevents vascular calcification by mitigating the biogenesis of calcifying EVs. We showed that EGFR inhibition reduces the release of pro-calcific CAV1-positive EVs and prevents calcification in osteogenic VSMC cultures and in chronic kidney disease mice fed a high-phosphate diet. EGFR inhibitors are clinically approved and widely used in cancer therapies and may represent an appropriate strategy to treat vascular calcification.




Previously Published In

Nik, Amirala Bakhshian, Hooi Hooi Ng, Patrick Sun, Francesco Iacoviello, Paul R. Shearing, Sergio Bertazzo, Deniel Mero, Bohdan B. Khomtchouk, and Joshua D. Hutcheson. "Epidermal Growth Factor Receptor Inhibition Prevents Caveolin-1-dependent Calcifying Extracellular Vesicle Biogenesis." bioRxiv (2021).

Bakhshian Nik, Amirala, Joshua D. Hutcheson, and Elena Aikawa. "Extracellular vesicles as mediators of cardiovascular calcification." Frontiers in cardiovascular medicine 4 (2017): 78.



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