Survivin Regulates Intracellular Stiffness and Extracellular Matrix Production in Vascular Smooth Muscle Cells

Authors

Amanda Krajnik, Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203, USA.
Erik Nimmer, Department of Biomedical Engineering, School of Engineering and Applied Sciences, University at Buffalo, Buffalo, New York 14260, USA.
Joseph A. Brazzo, Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203, USA.
John C. Biber, Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203, USA.
Rhonda Drewes, Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203, USA.
Bat-Ider Tumenbayar, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203, USA.
Andra Sullivan, Department of Biomedical Engineering, School of Engineering and Applied Sciences, University at Buffalo, Buffalo, New York 14260, USA.
Khanh Pham, Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203, USA.
Alanna Krug, Department of Biomedical Engineering, School of Engineering and Applied Sciences, University at Buffalo, Buffalo, New York 14260, USA.
Yuna Heo
John Kolega, Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203, USA.
Su-Jin Heo, Department of Orthopedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Kwonmoo Lee
Brian R. Weil, Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203, USA.
Deok-Ho Kim, Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland 21205, USA.Follow
Sachin A. Gupte, Department of Pharmacology, New York Medical College, Valhalla, New York 10595, USA.Follow
Yongho Bae

Author Type(s)

Faculty

DOI

10.1063/5.0157549

Journal Title

APL Bioengineering

First Page

046104

Document Type

Article

Publication Date

12-1-2023

Department

Pharmacology

Abstract

Vascular dysfunction is a common cause of cardiovascular diseases characterized by the narrowing and stiffening of arteries, such as atherosclerosis, restenosis, and hypertension. Arterial narrowing results from the aberrant proliferation of vascular smooth muscle cells (VSMCs) and their increased synthesis and deposition of extracellular matrix (ECM) proteins. These, in turn, are modulated by arterial stiffness, but the mechanism for this is not fully understood. We found that survivin is an important regulator of stiffness-mediated ECM synthesis and intracellular stiffness in VSMCs. Whole-transcriptome analysis and cell culture experiments showed that survivin expression is upregulated in injured femoral arteries in mice and in human VSMCs cultured on stiff fibronectin-coated hydrogels. Suppressed expression of survivin in human VSMCs significantly decreased the stiffness-mediated expression of ECM components related to arterial stiffening, such as collagen-I, fibronectin, and lysyl oxidase. By contrast, expression of these ECM proteins was rescued by ectopic expression of survivin in human VSMCs cultured on soft hydrogels. Interestingly, atomic force microscopy analysis showed that suppressed or ectopic expression of survivin decreases or increases intracellular stiffness, respectively. Furthermore, we observed that inhibiting Rac and Rho reduces survivin expression, elucidating a mechanical pathway connecting intracellular tension, mediated by Rac and Rho, to survivin induction. Finally, we found that survivin inhibition decreases FAK phosphorylation, indicating that survivin-dependent intracellular tension feeds back to maintain signaling through FAK. These findings suggest a novel mechanism by which survivin potentially modulates arterial stiffness.

Recommended Citation

Krajnik, A., Nimmer, E., Brazzo, J. A., Biber, J. C., Drewes, R., Tumenbayar, B., Sullivan, A., Pham, K., Krug, A., Heo, Y., Kolega, J., Heo, S., Lee, K., Weil, B. R., Kim, D., Gupte, S. A., & Bae, Y. (2023). Survivin Regulates Intracellular Stiffness and Extracellular Matrix Production in Vascular Smooth Muscle Cells. APL Bioengineering, 7 (4), 046104. https://doi.org/10.1063/5.0157549