Graduate Student Seminar Series – Vrushali Guruji

Graduate Student Seminar Series
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Location: 2nd Floor Auditorium (TRI/KITE) – 550 University Ave
Presentation Title: Analyzing the Impact of Hemodynamics in Bicuspid Aortic Valve Disease Associated Ascending Aortic Dilatation
Abstract: Bicuspid aortic valve (BAV) disease is characterized by two functioning leaflets instead of the normal three in a tricuspid aortic valve (TAV). Most BAV patients develop ascending aortic dilation (AAD), increasing their risk of fatal aortic dissection or rupture. We hypothesize that the elevated risk of developing AAD in BAV disease is a consequence of aberrant hemodynamics inducing gene perturbations in the aorta. To facilitate this investigation, a novel mouse model with a mutation in the natriuretic peptide 2 receptor (Npr2) was employed, enabling the isolation and evaluation of consequences accompanying aberrant blood flow. Notably, though genetically identical, 10% of Npr2+/- mice develop BAVs, whereas the remaining 90% have TAVs. To expedite the progression of BAV-AAD, mice are fed a high-fat western diet starting at 6 weeks of age. A novel echocardiogram protocol was developed to identify mice with BAVs or TAVs at 4 weeks of age, prior to diet introduction (Guruji et al., 2024). Next, the same echocardiogram protocol was performed on Npr2+/- mice at 6-weeks, 4-months and 5-months of age. Echo-particle image velocimetry (echo-PIV) was also done to track the patterns of blood flow more accurately and identify flow impingement zones. At 5 months of age, Npr2+/− mice with BAVs exhibited significantly elevated peak systolic velocities compared to TAV controls (2643 ± 392 vs. 1111 ± 146 mm/s, P < 0.05). Consistent with pathological remodeling, ascending aortic diameters were approximately 1.5-fold larger in Npr2+/−;BAV mice (1.75 ± 0.13 mm) compared to Npr2+/−;TAV mice (1.27 ± 0.01 mm), confirming BAV-associated AAD development. Aortic tissues from BAV and TAV mice were processed for spatial transcriptomic analysis using the Visium HD platform. Although data processing is ongoing, preliminary analyses indicate differential expression of canonical dilation-associated genes in dilated Npr2+/−;BAV aortas relative to non-dilated Npr2+/−;TAV controls. Specifically, COL1A1 expression was reduced in dilated aortas, whereas ELN and ACTA2 expression was increased. Next steps involve integrating spatial transcriptomic data with echo-PIV-defined flow impingement maps to identify hemodynamically regulated gene expression signatures. Candidate genes will be validated by immunohistochemical staining in 5-month-old Npr2+/− BAV and TAV aortas. Together, these studies aim to identify novel flow-dependent molecular drivers of AAD in BAV disease.
Supervisor Name: Craig A. Simmons
Year of Study: 4
Program of Study: PhD
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