Assistant Professor Fairfield University Fairfield, Connecticut, United States
Introduction: : Pulmonary hypertension is a condition where the blood pressure rises in the pulmonary arteries, often due to low oxygen levels or hypoxia. Hypoxia causes the arteries to thicken and therefore narrow which makes it difficult for blood to flow to the lungs, and this reduced blood flow puts a strain on the heart. Computational modeling can be a helpful tool in better understanding the effects of hypoxia on pulmonary artery growth and remodeling.
Materials and
Methods: : Computational models of cell signaling can be built and analyzed using Netflux and MATLAB to better understand the effects of hypoxia on pulmonary artery growth and remodeling. In these signaling network models, different peptides and stresses can be increased and decreased, enabling the changes to be closely observed and analyzed. A literature review was conducted specifically focused on hypoxia signaling cascades that can be included in computational models. This review enabled new species and reactions to be added to the VSMC network model, including the key species Notch, HIF-1A, PRR, FAT1, RTK/EGFR, and HIF-1B.
Results, Conclusions, and Discussions:: Results Incorporating new species into the computational model influenced how the signaling pathways behaved under perturbed conditions. An increase in Notch resulted in an increased activation of HIF-1α, a key regulator of the cellular response to hypoxia. This can be seen in Figure 1, where Notch activation is 0.2, and Figure 2, where Notch activation is 0.7. An increase in PRR caused an increased activation of multiple species: IKK, NFkB, HIF-2α, and HIF-1β. The species IKK and NF-kB help regulate immune and inflammatory responses while HIF-2α and HIF-1β are key components of the cellular response to hypoxia, (Dengler, Critical Reviews in Biochemistry and Molecular Biology, 2015). When FAT1 was increased, the activation of ROS, reactive oxygen species, also increased.
Conclusions Computational models can improve our understanding of hypoxia's effect on pulmonary artery growth and remodeling. The impact of different peptide hormones, like AngII, can be better observed and analyzed using Netflux and MATLAB, and the addition of new species allows for a better understanding of hypoxia's effect. This approach complements experimental research and could be further researched by changing other peptide hormones or proteins.
Discussions The perturbation of the new signaling pathways had varying effects on the model. The Notch signaling pathway is activated by hypoxia, (Guo, Front Oncol., 2023). When Notch activation was increased, HIF-1α activation also increased. HIF-1α serves as a transcription factor and is essential for different physiological processes like angiogenesis, (Basherruddin, Cureus, 2024). An increase in PRR caused an increase in multiple species: IKK, NFkB, HIF-2α, and HIF-1β. This indicates that PRR connects to both hypoxic and immune responses. An increase in FAT1 caused an increase in ROS, reactive oxygen species, which contributes to hypoxia.
Acknowledgements and/or References (Optional): : Basherruddin, Cureus, 2024 Dengler, Critical Reviews in Biochemistry and Molecular Biology, 2015 Guo, Front Oncol., 2023
