Survivin regulates intracellular stiffness and extracellular matrix production in vascular smooth muscle cells

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.

A microtubule stability switch alters isolated vascular smooth muscle calcium flux in response to matrix rigidity

“…Previous studies have shown that enhanced matrix stiffness promotes the dedifferentiation of VSMCs, downregulating contractile markers whilst increasing the expression of proliferative genes (Brown et al, 2010;Nagayama and Nishimiya, 2020;Sazonova et al, 2015;Xie et al, 2018). Increases VSMC migrational capacity, adhesion, proliferation and volume have also been reported (Brown et al, 2010;Krajnik et al, 2023;Nagayama and Nishimiya, 2020;Rickel et al, 2020;Sazonova et al, 2015;Wong et al, 2003). Furthermore, in response to matrix stiffness, VSMC reorganise their actin cytoskeleton and generate enhanced traction stresses, a finding we recapitulate in this study (Brown et al, 2010;Petit et al, 2019;Sanyour et al, 2019;Sazonova et al, 2015).…”

Phenotypic switching of vascular smooth muscle cells in atherosclerosis, hypertension, and aortic dissection

“…These include plateletderived growth factor BB (PDGF-BB), insulin-like growth factor (IGF), insulin receptor substrate (IRS), basic fibroblast growth factor (bFGF), Angiotensin II (Ang. II), epidermal growth factor (EGF), lysophosphatidic acid (LPA), heparan sulfate proteoglycan (HSPG), transforming growth factor-β 1 (TGF-β1), receptor tyrosine kinases (RTKs), G-protein coupled receptors (GPCRs), TGF-β receptor, as well as extracellular matrix (ECM) proteins like fibronectin, vimentin, Type IV collagen, and laminin (Beamish et al, 2009;Krajnik et al, 2023;McDaniel et al, 2007;Rabkin, 2023). Integrins and metalloproteinases are also well-known to control VSMC behavior and phenotype .…”