Assistant Professor Fairfield University Fairfield, Connecticut, United States
Introduction: : Mouse models are a key experimental tool for examining many biomedical abnormalities, such as the impact of hypoxia on the pulmonary artery. We were specifically interested in how hypoxia altered the genetic pathways and subsequent remodeling of the pulmonary artery in the mouse, Mus musculus. The purpose of this study was to research the interactions between 560 different hypoxia-associated genes from the pulmonary artery of Mus musculus. While many genes contribute to altered signaling due to hypoxia in Mus musculus, the exploration into the relationship between the gene pathways of each hypoxia gene is very valuable, especially in the context of vascular growth and remodeling. With an increased focus on the way in which specific genes have been expressed in the cardiovascular system, the vascular endothelial growth factor, Vegf, emerged as particularly important for pulmonary artery remodeling. While Vegf is essential for normal vascular development, this signaling cascade has been identified as a key pathway for hypoxia-induced remodeling that should be incorporated into our cell signaling network model.
Materials and
Methods: : We used bulk gene sequencing data provided by our experimental collaborator to guide this study. These data were obtained from mice exposed to a hypoxic chamber (FiO2: 10%) for 5 weeks, from 8 to 13 weeks of age. Through researching the interactions between hundreds of different hypoxia genes from the pulmonary artery of Mus musculus, many genes have been found to have similar characteristics including what each one enables, expresses, and activates. Patterns including the gene involvement in the development of varying systems in the body of Mus musculus, were identified within the hypoxia-associated genes in the pulmonary artery. The Vascular Endothelial Growth Factor (Vegf) pathway was further examined to determine how it is connected and works simultaneously with the pathways currently included vascular smooth muscle cell signaling network model. After examination of the connections of Vegf, it was determined through extensive research how Vegf was activated and regulated by existing species in the network model. Additionally, genes that enable and are involved in the Vascular Endothelial Growth Factor (Vegf) gene were identified and further evaluated within the 560 hypoxia-associated genes.
Results, Conclusions, and Discussions::
Results: We found different patterns of hypoxia-associated genes in the pulmonary artery and classified them into 6 relevant groupings associated with vascular growth and remodeling. We found that only two genes, Neuropillin-1 (Nrp1) and Activin receptor IIB (Acvr2b) were associated with vasculature development in the pulmonary artery of Mus musculus. In contrast, we found that the hypoxia-associated genes that were expressed in the cardiovascular system were substantial, totaling 30 genes (Table 1). Through our research, Vegf emerged as a particularly important addition to the existing cell signaling network model. We looked further into the connections between the Vegf and the vascular smooth muscle network and found relevant interactions with the stress input, integrins, FAK, P13K, Akt, and foxo (Figure 1). Each of these proteins played a prominent role in regulating and acting as receptors to facilitate responses within the house mice, Mus musculus.
Conclusions: When focusing directly on the way in which specific genes are expressed in the cardiovascular system, we found that Vegf, plays a prominent role in vascular development, and the genes that are enabled by the Vegf gene provided a foundation to explore how an alteration in oxygen levels is impacted and facilitated by these hypoxia-associated genes. Thus, we will incorporate the Vegf signaling pathway into the existing smooth muscle cell signaling network model, and we will use this model to further study the impact of hypoxia on cell and tissue remodeling.
Discussions: Identifying how altered gene expression leads to changes in cell and tissue remodeling is critical for understanding the effect of hypoxia on the pulmonary artery. While many genes will be useful to include in our cell signaling network model, specific ones, Vegf, Erythropoietin Receptor (Epor), and Bone Morphogenetic Protein 4 (Bmp4), provided a deeper insight into the way in which hypoxia and pulmonary hypertension can be further studied.
