A multiscale computational model of arterial growth and remodeling including Notch signaling.

Blood vessels grow and remodel in response to mechanical stimuli. Many computational models capture this process phenomenologically, by assuming stress homeostasis, but this approach cannot unravel the underlying cellular mechanisms. Mechano-sensitive Notch signaling is well-known to be key in vascular development and homeostasis. Here, we present a multiscale framework coupling a constrained mixture model, capturing the mechanics and turnover of arterial constituents, to a cell-cell signaling model, describing Notch signaling dynamics among vascular smooth muscle cells (SMCs) as influenced by mechanical stimuli. Tissue turnover was regulated by both Notch activity, informed by in vitro data, and a phenomenological contribution, accounting for mechanisms other than Notch. This novel framework predicted changes in wall thickness and arterial composition in response to hypertension similar to previous in vivo data. The simulations suggested that Notch contributes to arterial growth in hypertension mainly by promoting SMC proliferation, while other mechanisms are needed to fully capture remodeling. The results also indicated that interventions to Notch, such as external Jagged ligands, can alter both the geometry and composition of hypertensive vessels, especially in the short term. Overall, our model enables a deeper analysis of the role of Notch and Notch interventions in arterial growth and remodeling and could be adopted to investigate therapeutic strategies and optimize vascular regeneration protocols.

Notch signaling regulates strain-mediated phenotypic switching of vascular smooth muscle cells.

Mechanical stimuli experienced by vascular smooth muscle cells (VSMCs) and mechanosensitive Notch signaling are important regulators of vascular growth and remodeling. However, the interplay between mechanical cues and Notch signaling, and its contribution to regulate the VSMC phenotype are still unclear. Here, we investigated the role of Notch signaling in regulating strain-mediated changes in VSMC phenotype. Synthetic and contractile VSMCs were cyclically stretched for 48 h to determine the temporal changes in phenotypic features. Different magnitudes of strain were applied to investigate its effect on Notch mechanosensitivity and the phenotypic regulation of VSMCs. In addition, Notch signaling was inhibited via DAPT treatment and activated with immobilized Jagged1 ligands to understand the role of Notch on strain-mediated phenotypic changes of VSMCs. Our data demonstrate that cyclic strain induces a decrease in Notch signaling along with a loss of VSMC contractile features. Accordingly, the activation of Notch signaling during cyclic stretching partially rescued the contractile features of VSMCs. These findings demonstrate that Notch signaling has an important role in regulating strain-mediated phenotypic switching of VSMCs.

Mechano-regulated cell-cell signaling in the context of cardiovascular tissue engineering.

Cardiovascular tissue engineering (CVTE) aims to create living tissues, with the ability to grow and remodel, as replacements for diseased blood vessels and heart valves. Despite promising results, the (long-term) functionality of these engineered tissues still needs improvement to reach broad clinical application. The functionality of native tissues is ensured by their specific mechanical properties directly arising from tissue organization. We therefore hypothesize that establishing a native-like tissue organization is vital to overcome the limitations of current CVTE approaches. To achieve this aim, a better understanding of the growth and remodeling (G&R) mechanisms of cardiovascular tissues is necessary. Cells are the main mediators of tissue G&R, and their behavior is strongly influenced by both mechanical stimuli and cell-cell signaling. An increasing number of signaling pathways has also been identified as mechanosensitive. As such, they may have a key underlying role in regulating the G&R of tissues in response to mechanical stimuli. A more detailed understanding of mechano-regulated cell-cell signaling may thus be crucial to advance CVTE, as it could inspire new methods to control tissue G&R and improve the organization and functionality of engineered tissues, thereby accelerating clinical translation. In this review, we discuss the organization and biomechanics of native cardiovascular tissues; recent CVTE studies emphasizing the obtained engineered tissue organization; and the interplay between mechanical stimuli, cell behavior, and cell-cell signaling. In addition, we review past contributions of computational models in understanding and predicting mechano-regulated tissue G&R and cell-cell signaling to highlight their potential role in future CVTE strategies.

Microstructure of early embryonic aortic arch and its reversibility following mechanically altered hemodynamic load release.

In the embryonic heart, blood flow is distributed through a bilaterally paired artery system composed of the aortic arches (AAs). The purpose of this study is to establish an understanding of the governing mechanism of microstructural maturation of the AA matrix and its reversibility, toward the desired macroscopic vessel lumen diameter and thickness for healthy, abnormal, and in ovo repaired abnormal mechanical loading. While matrix-remodeling mechanisms were significantly different for normal versus conotruncal banding (CTB), both led to an increase in vessel lumen. Correlated with right-sided flow increase at Hamburger & Hamilton stages 21, intermittent load switching between collagen I and III with elastin and collagen-IV defines the normal process. However, decreases in collagen I, elastin, vascular endothelial growth factor-A, and fibrillin-1 in CTB were recovered almost fully following the CTB-release model, primarily because of the pressure load changes. The complex temporal changes in matrix proteins are illustrated through a predictive finite-element model based on elastin and collagen load-sharing mechanism to achieve lumen area increase and thickness increase resulting from wall shear stress and tissue strain, respectively. The effect of embryonic timing in cardiac interventions on AA microstructure was established where abnormal mechanical loading was selectively restored at the key stage of development. Recovery of the normal mechanical loading via early fetal intervention resulted in delayed microstructural maturation. Temporal elastin increase, correlated with wall shear stress, is required for continuous lumen area growth.NEW & NOTEWORTHY The present study undertakes comparative analyses of the mechanistic differences of the arterial matrix microstructure and dynamics in the three fundamental processes of control, conotruncal banded, and released conotruncal band in avian embryo. Among other findings, this study provides specific evidence on the restorative role of elastin during the early lumen growth process. During vascular development, a novel intermittent load-switching mechanism between elastin and collagen, triggered by a step increase in wall shear stress, governs the chronic vessel lumen cross-sectional area increase. Mimicking the fetal cardiovascular interventions currently performed in humans, the early release of the abnormal mechanical load rescues the arterial microstructure with time lag.

Asymmetry in Mechanosensitive Gene Expression during Aortic Arch Morphogenesis.

Embryonic aortic arches (AA) are initially bilaterally paired, transitional vessels and failures in remodeling based on hemodynamic and growth-related adaptations cause a spectrum of congenital heart disease (CHD) anatomies. Identifying regulatory mechanisms and cross-talk between the genetic elements of these vessels are critical to understand the ethiology of CHD and refine predictive computational models. This study aims to screen expression profiles of fundamental biological pathways in AA at early stages of chick embryo morphogenesis and correlate them with our current understanding of growth and mechanical loading. Reverse transcription-quantitative PCR (RT-qPCR) was followed by correlation and novel peak expression analyses to compare the behaviour and activation period of the genes. Available protein networks were also integrated to investigate the interactions between molecules and highlight major hierarchies. Only wall shear stress (WSS) and growth-correlated expression patterns were investigated. Effect of WSS was seen directly on angiogenesis as well on structural and apoptosis-related genes. Our time-resolved network suggested that WSS-correlated genes coordinate the activity of critical growth factors. Moreover, differential gene expression of left and right AA might be an indicator of subsequent asymmetric morphogenesis. These findings may further our understanding of the complex processes of cardiac morphogenesis and errors resulting in CHD.

Energy deficit in parvalbumin neurons leads to circuit dysfunction, impaired sensory gating and social disability.

Parvalbumin-expressing, fast spiking interneurons have high-energy demands, which make them particularly susceptible to energy impairment. Recent evidence suggests a link between mitochondrial dysfunction in fast spiking cortical interneurons and neuropsychiatric disorders. However, the effect of mitochondrial dysfunction restricted to parvalbumin interneurons has not been directly addressed in vivo. To investigate the consequences of mitochondrial dysfunction in parvalbumin interneurons in vivo, we generated conditional knockout mice with a progressive decline in oxidative phosphorylation by deleting cox10 gene selectively in parvalbumin neurons (PV-Cox10 CKO). Cox10 ablation results in defective assembly of cytochrome oxidase, the terminal enzyme of the electron transfer chain, and leads to mitochondrial bioenergetic dysfunction. PV-Cox10 CKO mice showed a progressive loss of cytochrome oxidase in cortical parvalbumin interneurons. Cytochrome oxidase protein levels were significantly reduced starting at postnatal day 60, and this was not associated with a change in parvalbumin interneuron density. Analyses of intrinsic electrophysiological properties in layer 5 primary somatosensory cortex revealed that parvalbumin interneurons could not sustain their typical high frequency firing, and their overall excitability was enhanced. An increase in both excitatory and inhibitory input onto parvalbumin interneurons was observed in PV-Cox10 CKO mice, resulting in a disinhibited network with an imbalance of excitation/inhibition. Investigation of network oscillations in PV-Cox10 CKO mice, using local field potential recordings in anesthetized mice, revealed significantly increased gamma and theta frequency oscillation power in both medial prefrontal cortex and hippocampus. PV-Cox10 CKO mice did not exhibit muscle strength or gross motor activity deficits in the time frame of the experiments, but displayed impaired sensory gating and sociability. Taken together, these data reveal that mitochondrial dysfunction in parvalbumin interneurons can alter their intrinsic physiology and network connectivity, resulting in behavioral alterations similar to those observed in neuropsychiatric disorders, such as schizophrenia and autism.