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Valve interstitial cell contractile strength and metabolic state are dependent on its shape.

ABSTRACT: The role of valvular interstitial cell (VIC) architecture in regulating cardiac valve function and pathology is not well understood. VICs are known to be more elongated in a hypertensive environment compared to those in a normotensive environment. We have previously reported that valve tissues cultured under hypertensive conditions are prone to acute pathological alterations in cell phenotype and contractility. We therefore aimed to rigorously study the relationship between VIC shape, contractile output and other functional indicators of VIC pathology. We developed an in vitro model to engineer VICs to take on the same shapes as those seen in normal and hypertensive conditions. VICs with longer cellular and nuclear shapes, as seen in hypertensive conditions, had greater contractile response to endothelin-1 that correlated with increased anisotropy of the actin architecture. These elongated VICs also demonstrated altered cell metabolism through a decreased optical redox ratio, which coincided with increased cellular proliferation. In the presence of actin polymerization inhibitor, however, these functional responses were significantly reduced, suggesting the important role of cytoskeletal actin organization in regulating cellular responses to abnormal shape. Overall, these results demonstrate the relationship between cell shape, cytoskeletal and nuclear organization, with functional output including contractility, metabolism, and proliferation.

SUBMITTER: Lam NT

PROVIDER: S-EPMC5096585 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Valve interstitial cell contractile strength and metabolic state are dependent on its shape.

Lam Ngoc Thien NT Muldoon Timothy J TJ Quinn Kyle P KP Rajaram Narasimhan N Balachandran Kartik K

Integrative biology : quantitative biosciences from nano to macro 20161001 10

The role of valvular interstitial cell (VIC) architecture in regulating cardiac valve function and pathology is not well understood. VICs are known to be more elongated in a hypertensive environment compared to those in a normotensive environment. We have previously reported that valve tissues cultured under hypertensive conditions are prone to acute pathological alterations in cell phenotype and contractility. We therefore aimed to rigorously study the relationship between VIC shape, contractil ...[more]

PMID: 27713997

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Project description:Valve interstitial cells (VIC) are the primary cell type residing within heart valve tissues. In many valve pathologies, VICs become activated and will subsequently profoundly remodel the valve tissue extracellular matrix (ECM). A primary indicator of VIC activation is the upregulation of ?-smooth muscle actin (?SMA) stress fibers, which in turn increase VIC contractility. Thus, contractile state reflects VIC activation and ECM biosynthesis levels. In general, cell contraction studies have largely utilized two-dimensional substrates, which are a vastly different micro mechanical environment than 3D native leaflet tissue. To address this limitation, hydrogels have been a popular choice for studying cells in a three-dimensional environment due to their tunable properties and optical transparency, which allows for direct cell visualization. In the present study, we extended the use of hydrogels to study the active contractile behavior of VICs. Aortic VICs (AVIC) were encapsulated within poly(ethylene glycol) (PEG) hydrogels and were subjected to flexural-deformation tests to assess the state of AVIC contraction. Using a finite element model of the experimental setup, we determined the effective shear modulus ? of the constructs. An increase in ? resulting from AVIC active contraction was observed. Results further indicated that AVIC contraction had a more pronounced effect on ? in softer gels (72?±?21% increase in ? within 2.5?kPa gels) and was dependent upon the availability of adhesion sites (0.5-1?mM CRGDS). The transparency of the gel allowed us to image AVICs directly within the hydrogel, where we observed a time-dependent decrease in volume (time constant ?=3.04 min) when the AVICs were induced into a hypertensive state. Our results indicated that AVIC contraction was regulated by both the intrinsic (unseeded) gel stiffness and the CRGDS peptide concentrations. This finding suggests that AVIC contractile state can be profoundly modulated through their local micro environment using modifiable PEG gels in a 3D micromechanical-emulating environment. Moving forward, this approach has the potential to be used towards delineating normal and diseased VIC biomechanical properties using highly tunable PEG biomaterials. STATEMENT OF SIGNIFICANCE.

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Valve interstitial cell contractile strength and metabolic state are dependent on its shape.

Publications

Valve interstitial cell contractile strength and metabolic state are dependent on its shape.

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