Coronary and Cerebral Arteriole Pathophysiological and Transcriptomic Adaptations in Intact vs. Ovariectomized Ossabaw Pigs with Cardiometabolic Heart Failure

Postmenopausal women pose a higher risk of developing heart failure with preserved ejection fraction (HFpEF) and associated cognitive decline. Previous data suggests pathological effects of HFpEF on both the heart and the brain are amplified with a loss of female sex hormones. The goal of this study was to determine the role of female sex hormones on coronary and cerebral arteriole pathological transcriptomic and functional adaptations in a clinically relevant porcine model of HFpEF with metabolic syndrome. Female Ossabaw swine were placed on a Western diet (high fat + high cholesterol) at approximately three months of age and underwent either aortic-banding (AB, n=4) at six months of age, or aortic-banding plus ovariectomy (AB-OVX, n=3). Ovariectomy occurred one month prior to the aortic-banding procedure. Animals were sacrificed six months post aortic-banding and coronary and cerebral vessels collected underwent further in vitro functional testing. Both coronary and cerebral vessels were isolated, pressurized, and exposed to increasing doses of sodium nitroprusside (SNP, nitric oxide mimetic), or U46619 (thromboxane 2A agonist) to assess endothelial-independent vascular function. SNP-induced dilation was reduced in AB-OVX compared to AB (coronary 87.6% vs. 97.8%; cerebral 26.9% vs. 83.6%; two-way ANOVA Group Main Effect and Group x Dose Interaction) and U46619-induced constriction was also reduced in AB-OVX compared to AB (cerebral 38.0% vs. 50.7%; two-way ANOVA Group Main Effect). RNA seq identified 286 differentially expressed genes (DEGs) in cerebral arterioles and 17 DEGs in coronary arterioles. Ingenuity pathway analysis (IPA) on cerebral arterioles predicted inhibition of Brain-derived Neurotrophic Factor (BDNF) (z-score > -2), a gene regulated by estradiol. BDNF inhibition was correlated with various downstream affects including decreased cognition, increased peripheral vascular disease, and increased fibrosis of the heart in AB-OVX animals. IPA in the coronary arterioles revealed decreased expression of upstream regulator Dual Specificity Phosphatase 1 (DUSP1), a critical signaling effector of the heart involved in p38 mitogen-activated protein kinase (MAPK) activity and vascular apoptosis. These findings indicate distinct pathological transcriptomic and functional adaptations in Cardiometabolic HFpEF with the loss of female sex hormones and suggest genes associated with BDNF and DUSP1 are potential therapeutic targets. MU Tier 1 Sequencing Grant, Department of Defense (DOD) Grant W81XWH-18-1-1079, and IDEXX-BioAnalytics This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.