Endothelial cell-specific MnSOD overexpression can prevent monocrotaline-induced pulmonary hypertension

Objective: Increased mitochondrial reactive oxygen species (ROS) is a known contributor to endothelial cell (EC) dysfunction, which plays a major role in the development and progression of pulmonary hypertension (PH). Deficiency of mitochondrial antioxidant MnSOD has been linked to pathological pulmonary vascular remodeling in PH. The objective of this study was to determine whether EC-specific transgenic overexpression of MnSOD attenuates the onset and progression of PH. Hypothesis: MnSOD overexpression in ECs will attenuate the development of PH. Methods: We studied binary conditional transgenic animals with EC-specific MnSOD overexpression inducible by a Tet-OFF system. Mice of both sexes were divided into groups MnSODVE-NE (normal expression of MnSOD in EC) and MnSODVE-OE (overexpression of MnSOD in EC). PH was induced in both groups by weekly subcutaneous injection of monocrotaline (60 mg/kg) for 4 weeks. At the end of this period, echocardiography was performed, and the organs were collected for morphometric and histological analyses. Results: Animals overexpressing MnSOD in EC showed an 11% decrease in RV hypertrophy (0.31±0.01 in MnSOD-NE vs. 0.27±0.006 in MnSOD-OE, p=0.0164) and a 44% decrease in pulmonary vascular remodeling (18.43±0.80 in MnSOD-NE vs. 10.27±0.87 in MnSOD-OE, p=0.0001) compared to control. Echocardiographic assessment showed a 25% increase in PAT/PET ratio (0.24±0.01 in MnSOD-NE vs. 0.30±0.02 in MnSOD-OE, p=0.0276) and a 49% increase in TAPSE (0.74±0.08 in MnSOD-NE vs. 1.1±0.03 in MnSOD-OE, p=0.0020), indicating that EC-specific MnSOD OE was able to attenuate the development of monocrotaline-induced PH. This beneficial effect was related to a 61% increased expression of CPT1A (0.62±0.05 in MnSOD-NE vs. 1.01±0.10 in MnSOD-OE, p=0.006). Conclusion(s): EC-specific MnSOD overexpression was effective in preventing pulmonary vascular remodeling and attenuating the development of PH in mice. R56HL133624, 5P30GM145500, RI fdn 1472420231352; Bray Award-Brown Univ.; T32HL160517, R01HL046716; T32GM065085; CAPES/PRINT 88887.363181/2019-00; CNPq 404484/2021-2 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.