Dataset Information

TiO2-Based Nanotopographical Cues Attenuate the Restenotic Phenotype in Primary Human Vascular Endothelial and Smooth Muscle Cells.

ABSTRACT: Coronary and peripheral stents are implants that are inserted into blocked arteries to restore blood flow. After stent deployment, the denudation of the endothelial cell (EC) layer and the resulting inflammatory cascade can lead to restenosis, the renarrowing of the vessel wall due to the hyperproliferation and excessive matrix secretion of smooth muscle cells (SMCs). Despite advances in drug-eluting stents (DES), restenosis remains a clinical challenge and can require repeat revascularizations. In this study, we investigated how vascular cell phenotype can be modulated by nanotopographical cues on the stent surface, with the goal of developing an alternative strategy to DES for decreasing restenosis. We fabricated TiO2 nanotubes and demonstrated that this topography can decrease SMC surface coverage without affecting endothelialization. In addition, to our knowledge, this is the first study reporting that TiO2 nanotube topography dampens the response to inflammatory cytokine stimulation in both endothelial and smooth muscle cells. We observed that compared to flat titanium surfaces, nanotube surfaces attenuated tumor necrosis factor alpha (TNF?)-induced vascular cell adhesion molecule-1 (VCAM-1) expression in ECs by 1.8-fold and decreased TNF?-induced SMC growth by 42%. Further, we found that the resulting cellular phenotype is sensitive to changes in nanotube diameter and that 90 nm diameter nanotubes leads to the greatest magnitude in cell response compared to 30 or 50 nm nanotubes.

SUBMITTER: Cao Y

PROVIDER: S-EPMC7288980 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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TiO<sub>2</sub>-Based Nanotopographical Cues Attenuate the Restenotic Phenotype in Primary Human Vascular Endothelial and Smooth Muscle Cells.

Cao Yiqi Y Desai Tejal A TA

ACS biomaterials science & engineering 20200117 2

Coronary and peripheral stents are implants that are inserted into blocked arteries to restore blood flow. After stent deployment, the denudation of the endothelial cell (EC) layer and the resulting inflammatory cascade can lead to restenosis, the renarrowing of the vessel wall due to the hyperproliferation and excessive matrix secretion of smooth muscle cells (SMCs). Despite advances in drug-eluting stents (DES), restenosis remains a clinical challenge and can require repeat revascularizations. ...[more]

PMID: 32529030

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Project description:ObjectiveWe examined the role of syndecan-1 in modulating the phenotype of vascular smooth muscle cells in the context of endogenous inflammatory factors and altered microenvironments that occur in disease or injury-induced vascular remodeling.Methods and resultsVascular smooth muscle cells (vSMCs) display a continuum of phenotypes that can be altered during vascular remodeling. While the syndecans have emerged as powerful and complex regulators of cell function, their role in controlling vSMC phenotype is unknown. Here, we isolated vSMCs from wild type (WT) and syndecan-1 knockout (S1KO) mice. Gene expression and western blotting studies indicated decreased levels of α-smooth muscle actin (α-SMA), calponin, and other vSMC-specific differentiation markers in S1KO relative to WT cells. The spread area of the S1KO cells was found to be greater than WT cells, with a corresponding increase in focal adhesion formation, Src phosphorylation, and alterations in actin cytoskeletal arrangement. In addition, S1KO led to increased S6RP phosphorylation and decreased AKT and PKC-α phosphorylation. To examine whether these changes were present in vivo, isolated aortae from aged WT and S1KO mice were stained for calponin. Consistent with our in-vitro findings, the WT mice aortae stained higher for calponin relative to S1KO. When exposed to the inflammatory cytokine TNF-α, WT vSMCs had an 80% reduction in syndecan-1 expression. Further, with TNF-α, S1KO vSMCs produced increased pro-inflammatory cytokines relative to WT. Finally, inhibition of interactions between syndecan-1 and integrins αvβ3 and αvβ5 using the inhibitory peptide synstatin appeared to have similar effects on vSMCs as knocking out syndecan-1, with decreased expression of vSMC differentiation markers and increased expression of inflammatory cytokines, receptors, and osteopontin.ConclusionsTaken together, our results support that syndecan-1 promotes vSMC differentiation and quiescence. Thus, the presence of syndecan-1 would have a protective effect against vSMC dedifferentiation and this activity is linked to interactions with integrins αvβ3 and αvβ5.

Project description:RATIONALE:The phenotypes of vascular smooth muscle cells (vSMCs) comprise a continuum bounded by predominantly contractile and synthetic cells. Some evidence suggests that contractile vSMCs can assume a more synthetic phenotype in response to ischemic injury, but the mechanisms that activate this phenotypic switch are poorly understood. OBJECTIVE:To determine whether lactate, which increases in response to regional ischemia, may promote the synthetic phenotype in vSMCs. METHODS AND RESULTS:Experiments were performed with vSMCs that had been differentiated from human induced pluripotent stem cells and then cultured in glucose-free, lactate-enriched (L+) medium or in standard (L-) medium. Compared with the L- medium, the L+ medium was associated with significant increases in synthetic vSMC marker expression, proliferation, and migration and with significant declines in contractile and apoptotic activity. Furthermore, these changes were accompanied by increases in the expression of monocarboxylic acid transporters and were generally attenuated both by the blockade of monocarboxylic acid transporter activity and by transfection with iRNA for NDRG (N-myc downstream regulated gene). Proteomics, biomarker, and pathway analyses suggested that the L+ medium tended to upregulate the expression of synthetic vSMC markers, the production of extracellular proteins that participate in tissue construction or repair, and the activity of pathways that regulate cell proliferation and migration. Observations in hypoxia-cultured vSMCs were similar to those in L+-cultured vSMCs, and assessments in a swine myocardial infarction model suggested that measurements of lactate levels, lactate-dehydrogenase levels, vSMC proliferation, and monocarboxylic acid transporter and NDRG expression were greater in the ischemic zone than in nonischemic tissues. CONCLUSIONS:These results demonstrate for the first time that vSMCs assume a more synthetic phenotype in a microenvironment that is rich in lactate. Thus, mechanisms that link glucose metabolism to vSMC phenotypic switching could play a role in the pathogenesis and treatment of cardiovascular disease.

Project description:The cardiovascular disease of atherosclerosis is characterised by aged vascular smooth muscle cells and compromised cell survival. Analysis of human and murine plaques highlights markers of DNA damage such as p53, Ataxia telangiectasia mutated (ATM), and defects in mitochondrial oxidative metabolism as significant observations. The antiageing protein Klotho could prolong VSMC survival in the atherosclerotic plaque and delay the consequences of plaque rupture by improving VSMC phenotype to delay heart attacks and stroke. Comparing wild-type VSMCs from an ApoE model of atherosclerosis with a flox'd Pink1 knockout of inducible mitochondrial dysfunction we show WT Pink1 is essential for normal cell viability, while Klotho mediates energetic switching which may preserve cell survival. Wild-type ApoE VSMCs were screened to identify potential drug candidates that could improve longevity without inducing cytotoxicity. The central regulator of cell metabolism AMP Kinase was used as a readout of energy homeostasis. Functional energetic switching between oxidative and glycolytic metabolism was assessed using XF24 technology. Live cell imaging was then used as a functional readout for the WT drug response, compared with Pink1 (phosphatase-and-tensin-homolog (PTEN)-induced kinase-1) knockout cells. Candidate drugs were assessed to induce pACC, pAMPK, and pLKB1 before selecting Klotho for its improved ability to perform energetic switching. Klotho mediated an inverse dose-dependent effect and was able to switch between oxidative and glycolytic metabolism. Klotho mediated improved glycolytic energetics in wild-type cells which were not present in Pink1 knockout cells that model mitochondrial dysfunction. Klotho improved WT cell survival and migration, increasing proliferation and decreasing necrosis independent of effects on apoptosis. Klotho plays an important role in VSMC energetics which requires Pink1 to mediate energetic switching between oxidative and glycolytic metabolism. Klotho improved VSMC phenotype and, if targeted to the plaque early in the disease, could be a useful strategy to delay the effects of plaque ageing and improve VSMC survival.

Dataset Information

TiO2-Based Nanotopographical Cues Attenuate the Restenotic Phenotype in Primary Human Vascular Endothelial and Smooth Muscle Cells.

Publications

TiO<sub>2</sub>-Based Nanotopographical Cues Attenuate the Restenotic Phenotype in Primary Human Vascular Endothelial and Smooth Muscle Cells.

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