Biology subjects

LaDisa, J. F.

Publications and source records attributed to LaDisa, J. F..

2 recordsLinked to original sources

bioRxiv2024

Activity and function of the endothelial sodium channel is regulated by the effector domain of MARCKS like protein 1 in mouse aortic endothelial cells

The endothelial sodium channel (EnNaC) plays an important role in regulating vessel stiffness. Here, we investigated the regulation of EnNaC in mouse aortic endothelial cells (mAoEC) by the actin cytoskeleton and lipid raft association protein myristoylated alanine-rich C-kinase substrate like protein 1 (MLP1). We hypothesized that mutation of specific amino acid residues within the effector domain of MLP1 or loss of association between MLP1 and the anionic phospholipid phosphate PIP2 would significantly alter membrane association and EnNaC activity in mAoEC. mAoEC transiently transfected with a mutant MLP1 construct (three serine residues in the effector domain replaced with aspartate residues) showed a significant decrease in EnNaC activity compared to cells transfected with wildtype MLP1. Compared to vehicle treatment, mAoEC treated with the PIP2 synthesis blocker wortmannin showed less colocalization of EnNaC and MLP1. In other experiments, Western blot and densitometric analysis showed a significant decrease in MLP1 and caveloin-1 protein expression in mAoEC treated with wortmannin compared to vehicle. Finally, wortmannin treatment decreased sphingomyelin content and increased membrane fluidity in mAoEC. Taken together, our results suggest constitutive phosphorylation of MLP1 attenuates the function of EnNaC in aortic endothelial cells by a mechanism involving a decrease in association with MLP1 and EnNaC at the membrane, while deletion of PIP2 decreases MARCKS expression and overall membrane fluidity.

physiology↗

bioRxiv2023

A Computational Model of Coarctation of the Aorta in Rabbits: Ventricular and Ascending Aortic Remodeling

Coarctation of the aorta (CoA) is a common congenital cardiovascular lesion that typically presents as a localized narrowing of the proximal descending thoracic aorta just distal to the left subclavian artery. While improvements in surgical and catheter-based techniques have increased short-term survival, there is a high long-term risk of hypertension after CoA correction and a reduced average lifespan despite treatment. Computational models can be used to estimate ventricular and arterial remodeling, potentially serving as key tools in developing a mechanistic understanding of the interplay between pre-correction hemodynamics, post-correction recovery, and long-term hypertension risk. In this study, we developed a lumped parameter model of the heart and circulation to simulate aortic coarctation. We then used the model to estimate changes in ventricular thickness and ascending aortic compliance from imaging and catheterization data collected in rabbits with untreated and corrected CoA that used the current putative clinical treatment threshold ([≥]20 mmHg). Model outputs were compared to reported stroke volume, ejection fraction, systolic and diastolic ascending aortic pressures, peak ascending aortic flow, mean and peak aortic blood pressure gradients, and upper-to-lower body flow split, with all results falling within one standard deviation of the data for control, untreated CoA, and corrected CoA groups. In the untreated CoA and corrected simulations, a decrease in ascending aortic compliance was necessary to match reported hemodynamics, suggesting the rabbits exposed to CoA [≥]20 mmHg underwent vascular remodeling that persisted after repair.

bioengineering↗