Calcific aortic valve disease (CAVD) affects 25% of people over 65, and the late-stage stenotic state can only be treated with total valve replacement, requiring 85,000 surgeries annually in the US alone [1]. As CAVD is an age-related disease, many of the affected patients are unable to undergo the open-chest surgery that is its only current cure. This challenge motivates the elucidation of the mechanisms involved in calcification, with the eventual goal of alternative preventative and therapeutic strategies. There is no sufficient animal model of CAVD, so we turn to potential in vitro models. In general, in vitro models have the advantages of shortened experiment time and better control over multiple variables compared to in vivo models. As with all models, the hypothesis being tested dictates the most important characteristics of the in vivo physiology to recapitulate. Here, we collate the relevant pieces of designing and evaluating aortic valve calcification so that investigators can more effectively draw significant conclusions from their results.
Cadherin-11 (CDH11) is upregulated in a variety of fibrotic diseases, including arthritis and calcific aortic valve disease. Our recent work has identified CDH11 as a potential therapeutic target and shown that treatment with a CDH11 functional blocking antibody can prevent hallmarks of calcific aortic valve disease in mice. The present study investigated the role of CDH11 in regulating the mechanobiological behavior of valvular interstitial cells believed to cause calcification. Aortic valve interstitial cells were harvested from Cdh11+/+, Cdh11+/−, and Cdh11−/− immortomice. Cells were subjected to inflammatory cytokines transforming growth factor (TGF)-β1 and IL-6 to characterize the molecular mechanisms by which CDH11 regulates their mechanobiological changes. Histology was performed on aortic valves from Cdh11+/+, Cdh11+/−, and Cdh11−/− mice to identify key responses to CDH11 deletion in vivo. We showed that CDH11 influences cell behavior through its regulation of contractility and its ability to bind substrates via focal adhesions. We also show that transforming growth factor-β1 overrides the normal relationship between CDH11 and smooth muscle α-actin to exacerbate the myofibroblast disease phenotype. This phenotypic switch is potentiated through the IL-6 signaling axis and could act as a paracrine mechanism of myofibroblast activation in neighboring aortic valve interstitial cells in a positive feedback loop. These data suggest CDH11 is an important mediator of the myofibroblast phenotype and identify several mechanisms by which it modulates cell behavior. NEW & NOTEWORTHY Cadherin-11 influences valvular interstitial cell contractility by regulating focal adhesions and inflammatory cytokine secretion. Transforming growth factor-β1 overrides the normal balance between cadherin-11 and smooth muscle α-actin expression to promote a myofibroblast phenotype. Cadherin-11 is necessary for IL-6 and chitinase-3-like protein 1 secretion, and IL-6 promotes contractility. Targeting cadherin-11 could therapeutically influence valvular interstitial cell phenotypes in a multifaceted manner.
Infrared neural stimulation (INS) is becoming an important complementary tool to electrical stimulation. Since the mechanism of INS is photothermal, describing the laser-induced heat distribution is fundamental to determining the relationship between stimulation pulses and neural responses. This work developed both a framework describing the time evolution of the heat distribution induced by optical fluence and a new method to extract thermal criteria (e.g., temperature change and rate of change) for neural activation. To solve the general problem of describing the temperature distribution, a Green's function solution to the heat diffusion equation was determined and convolved with the optical fluence. This provided a solution in the form of a single integral over time, from which closed-form solutions can be determined for special cases. This work also yielded an expression for thermal relaxation time, which provides a rigorous description of thermal confinement for INS. The developed framework was then applied to experimental data from the cochlea to extract the minimum temperature increase and rate of that increase to stimulate the cochlear spiral ganglion. This result, and similar analyses applied to other neural systems, can then shed light on the fundamental mechanism for INS and aid the development of optical neuroprostheses.
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