Hypoxia-induced Ventricular Hypertrophy in Wild-type and Caveolin-1 Knockout Mice

Background: Hypoxic lung diseases often induce the development of right ventricular (RV) hypertrophy and pulmonary hypertension. Hypoxia has been shown to increase mitogenic and fibrogenic signaling in heart muscle, resulting in ventricular hypertrophy. Caveolin-1, a structural and scaffolding protein required for caveolae formation, regulates heart function by controlling mitogenic signaling and other important signaling pathways, including nitric oxide production, inflammation, and oxidative stress. Our lab and other researchers have shown that decreased caveolin-1 (Cav1) expression is associated with developing pulmonary hypertension. In the current study, we sought to determine the potential role of Cav1 in protecting the heart from hypoxia-induced ventricular hypertrophy. Methods: To test this hypothesis, we conducted two experiments. In the first one, we used global Cav1 knockout (Cav1-KO), EC-Cav1-reconstituted (Cav1-RC), and wild-type (WT) mice (6-8 weeks old; 4 males and 4 females per group). In the second one, we used endothelial cell-specific (EC)-Cav1 -/- mice and wild-type mice (6-8 weeks old; 4 males and 4 females per group) that were exposed to hypoxia (10% O 2 ) or normoxia (21% O 2 ) for up to 8 weeks. Histological sections of the heart were scanned and analyzed for right ventricular (RV) and left ventricular (LV) thickness. Data were analyzed using two-way ANOVA and Tukey’s post hoc analysis. Results: Data from the first experiment showed that female Cav1 KO mice exhibited a 17% and 11.6% increase in RV and LV thickness, respectively. Female EC-Cav1-RC showed a significant reduction in the RV thickness (average: -19.6%, p -value=0.006) compared to the Cav1-KO. On the other hand, there were no statistically significant differences in LV or RV thickness in male mice. Data from the second experiment showed increased RV thickness in male and female WT mice under hypoxic conditions (33% and 14.5%, respectively), compared to those under normoxic conditions. Female mice were more sensitive to EC-Cav1 knockout, showing a 21% increase in RV thickness compared to WT mice, while male mice did not show comparable changes. EC-Cav1 KO female mice did not demonstrate a further increase in LV or RV thickness in response to hypoxia. On the other hand, male mice, whether WT or EC-Cav1 KO, exhibited a greater hypoxia, showing an increase in RV thickness of 33% and 48%, respectively. Hypoxia also impacted the LV thickness in male and female WT mice, causing a marked increase of 47% and 22%, respectively. Finally, an interaction between hypoxia and EC-Cav1 KO was observed in female mice, where LV thickness increased by 27% compared to normoxic WT female mice. Conclusions: This study suggests a specific role for EC Cav1 expression in female mice in protecting against hypoxia-induced myocardial hypertrophy. Further experiments with a larger sample size are warranted to reach statistical significance and a definitive conclusion. This work was supported by National Institutes of Health National Heart, Lung and Blood Institute grants HL125356 and HL142636 (R.D.M.) 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.