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.

Quantifying heart valve interstitial cell contractile state using highly tunable poly(ethylene glycol) hydrogels

“…With the current hydrogel chemistry used in this study, the stiffness and stress-relaxation properties are coupled and tunable through adjusting the concentration of MMP-degradable crosslinks, which does not allow us to uniquely study the effects of these two parameters separately. However, it is clear that the mechanics of the culture environment plays a large role in regulating AVIC shape, which has been shown previously to be a key regulator of AVIC contraction at the population [14] and the single cell level [15]. Tandon et al report that when AVICs were cultured within thin micropatterned protein lines (10 μm wide), this led to increased cell and nuclear aspect ratios as compared to AVICs seeded within wider lines (80 μm wide) [14].…”

“…Despite the important biosynthetic role that VICs play in regulating valve tissue structure and function, little is known about VIC mechanobiology within the actual complex native 3D micro-environment. To date, VIC mechanical properties have primarily been studied exvivo using 2D techniques such as traction force microscopy [13], two-dimensional cantilever experiments [14], and micro-patterned island arrays [15]. Despite the valuable knowledge gained from these studies, the 2D substrate environment is very different to the native 3D valve leaflet and does not replicate the complexity of the 3D responses.…”

Dexfenfluramine and Pergolide Cause Heart Valve Disease via Valve Metabolic Reprogramming and Ongoing Matrix Remodeling

“…For instance, RhoA signaling drives heart valve calcification [21], and mutations in Flna [22] and Dchs1 [23] encoding a cadherin and a cytoskeleton protein involved in mechanotransduction, respectively, both lead to the development of myxomatous valve disease. Strikingly, VIC elongation that occurs under hypertensive conditions was associated with altered cell metabolism [24].…”

Valve leaflet‐inspired elastomeric scaffolds with tunable and anisotropic mechanical properties

“…These biophysical and biomechanical cues also determine the behavior of valvular cells. The phenotype of valvular interstitial cells (VICs), the most abundant and plastic cell population in the valve, can be modulated by the properties of cell culture substrate/matrix . It has been revealed that matrix stiffness affects the activation and osteogenic differentiation of VICs .…”

“…The phenotype of valvular interstitial cells (VICs), the most abundant and plastic cell population in the valve, can be modulated by the properties of cell culture substrate/matrix. 6,7 It has been revealed that matrix stiffness affects the activation and osteogenic differentiation of VICs. [8][9][10] Moreover, the morphology and architecture of valvular ECM have been shown to instruct the attachment and spreading of VICs.…”