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Women's Health

Women's Health - Poster Session C & D

Z46 - Sex-Based Differences in Left Heart Failure Induced Pulmonary Vascular Remodeling

Friday, October 10, 2025
10:00 AM - 11:00 AM PDT
Location: Exhibit Hall F, G & H

    Presenting Author(s)

  • Ekin E. Atila

    Undergraduate Student
    University of California Irvine, United States

    • Co-Author(s)

  • FT

    Fernando Trinidad

    Graduate Student
    University of California Irvine, United States

    • Primary Investigator(s)

  • Naomi C. Chesler, PhD

    Professor
    University of California, Irvine
    Irvine, California, United States


Introduction: : A significant gap in knowledge remains regarding the sex-specific mechanisms of Left Heart Failure (LHF)-associated pulmonary hypertension (PH), warranting further investigation on sex-based cardiopulmonary pathophysiology. Despite being at greater risk of developing LHF-PH, women display better disease post-diagnosis outcomes than men. In this study, I aim to elucidate sex-based cardiopulmonary health differences using myocardial infarction (MI) animal models, in which localized MI-induced left ventricular ischemia progresses to isolated postcapillary PH and, if untreated, combined post- and precapillary PH (CpcPH). This progression drives pulmonary vascular remodeling, where endothelial cells undergo endothelial-to-mesenchymal transition (EndoMT) to repair tissue damage caused by hypoxia, which promotes EndoMT by activating fibrotic signaling pathways. During remodeling, the increased deposition of collagen fibers and decrease in elastin fibers contribute to the restructuring of the extracellular matrix (ECM). The basal lamina, a thin ECM layer that fosters cell flexibility and movement, is degraded by matrix metalloproteinases (MMPs). New matrix molecules, such as Type I and Type III collagen, replace the basal lamina and encourage EndoMT by activating signaling receptors. To assess collagen, I performed histological staining on sectioned left lung tissues and analyzed fiber deposition and sex based trends using light microscopy. I hypothesize that female mice will demonstrate reduced collagen synthesis in pulmonary arteries compared to males following MI, potentially contributing to their improved prognosis.

Materials and

Methods: : A cohort of 10 C57BL/6 mice (Jackson Labs), consisting of 5 females and 5 males, was studied. Within each sex, n=2 served as controls and n=3 underwent MI via left coronary artery ligation. Animals were euthanized 24 weeks post-surgery, and lungs were harvested, fixed in formalin at a pressure of 20 cm H2O, and paraffin-embedded. Thin sections (5 microns) were then cut using a microtome, and Picrosirius Red Staining was performed (following ABCAM protocol) to visualize collagen. The stained lungs were observed using light microscopy, and the percentage of collagen present in the vessel was quantified using ImageJ.

Images were background-corrected, and collagen was isolated using color deconvolution. The vessel wall was traced utilizing the polygon tool, and the lumen was subtracted to isolate the vessel wall. A macro was used to quantify collagen within the vessel wall, and this value was then divided by the vessel wall area to determine the percentage of collagen.

To account for heterogeneity in pulmonary vascular composition, vessels were categorized on lumen size. Direct comparison of collagen decomposition across vessels of varying diameters is confounded by size-dependent differences in extracellular matrix composition. Thus, we used K-means (Python) clustering to categorize vessel data into three groups based on lumen area, enabling size-normalized collagen quantification. K-means clustering groups identify inherent similarities in measured parameters (e.g., lumen dimensions).

Results, Conclusions, and Discussions:: This small cohort revealed sex-specific collagen remodeling patterns; post-MI females exhibited a 13% increase in collagen compared to control females (MI: 0.31 ± .06; Control: 0.28 ± 0.12 collagen-to-wall ratio), while post-MI males showed a 20% decrease compared to control males (MI: 0.33 ± .05; Control: 0.41 ± .12 collagen-to-wall ratio). Notably, post-MI females demonstrated more mesenchymal transition, as indicated by increased collagen, than males, a result that is inconsistent with their potentially better disease prognosis.

This discrepancy - where our raw data suggest confounding results with established literature - highlights two critical limitations: (1) insufficient statistical power due to small sample size, and (2) unaccounted confounding variables in cross-study comparison. A power analysis between MI and Control females reveals that a cohort of 42 mice (21 per group) would be required to achieve 80% power for detecting significant differences in collagen composition post-MI. In addition, fluorescent immunohistochemistry can help quantify EndoMT markers (CD31, VE-cadherin, and alpha-SMA). This would support the claim of sex-dependent expression of EndoMT. Additionally, visualizing collagen fibers under polarized light microscopy will allow for the differentiation between type 1 and type 3 collagen, providing more details on collagen synthesis between sexes. In conclusion, these findings provide preliminary insight into sex-based disparities in cardiopulmonary health, providing an incentive for further investigation.

Acknowledgements and/or References (Optional): : I would like to acknowledge Dr. Cassandra K. Conway-O’Donnell, Leticia Charco, and all members of the Chesler Lab for their contributions and support. This research was funded and supported by the Undergraduate Research Opportunity Program (UROP), University of California, Irvine.