Abstract
Animal models that recapitulate human diseases and disorders are widely used to investigate etiology, diagnosis, and treatment of those conditions in people. Disorders during pregnancy are particularly difficult to explore as interventions in pregnant women are not easily performed. Therefore, models that allow for pre-conception investigations are advantageous for elucidating the mechanisms involved in adverse pregnancy outcomes that are responsible for both maternal and fetal morbidity, such as preeclampsia. The Blood Pressure High (BPH)/5 mouse model has been used extensively to study the pathogenesis of preeclampsia. The female BPH/5 mouse is obese with increased adiposity and borderline hypertension, both of which are exacerbated with pregnancy making it a model of superimposed preeclampsia. Thus, the BPH/5 model shares traits with a large majority of women with pre-existing conditions that predisposes them to preeclampsia. We sought to explore the genome of the BPH/5 female mouse and determine the genetic underpinnings that may contribute to preeclampsia-associated phenotypes in this model. Using a whole genome sequencing approach, we are the first to characterize the genetic mutations in BPH/5 female mice that make it unique from the closely related BPH/2 model and the normotensive background strain, C57Bl/6. We found the BPH/5 female mouse to be uniquely different from BPH/2 and C57Bl/6 mice with a genetically complex landscape. The majority of non-synonymous consequences within the coding region of BPH/5 females were missense mutations found most abundant on chromosome X when comparing BPH/5 and BPH/2, and on chromosome 8 when comparing BPH/5 to C57Bl/6. Genetic mutations in BPH/5 females largely belong to immune system-related processes, with overlap between BPH/5 and BPH/2 models. Further studies examining each gene mutation during pregnancy are warranted to determine key contributors to the BPH/5 preeclamptic-like phenotype and to identify genetic similarities to women that develop preeclampsia.
Highlights
Hypertensive mice have long been utilized as translational models to investigate blood pressure regulation
We identified chromosomal variants in Blood Pressure High (BPH)/5 females that may contribute to genetic mutations and alterations in the proteome
All animals were maintained according to Louisiana State University Institutional Animal Care and Use Committee (IACUC) approved standards
Summary
Hypertensive mice have long been utilized as translational models to investigate blood pressure regulation. The closely related strains Blood Pressure High (BPH)/2, Blood Pressure Normal (BPN)/3, and Blood Pressure Low (BPL)/1 mice, with different cardiovascular and metabolic profiles, are examples [1]. These strains were established after 23 generations of two-way selection for high and low systolic blood pressure. Female BPL/1 mice have hypotension compared to normotensive BPN/3 [3] These strains have been used to investigate the mechanisms that lead to hypertension in humans [4,5,6,7,8,9]. One of these sublines was identified as BPH/5, which have lower blood pressures than BPH/2 mice, with female mice considered “borderline hypertensive” with mean arterial pressure ranging from 103 to 119 mmHg as measured by radiotelemetry [10,11]
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