Reverse pulmonary vascular remodeling in pulmonary hypertension due to left heart disease identifies PGC1α and ERRγ as putative therapeutic targets

Background: Pulmonary hypertension (PH) due to left heart disease (PH-LHD) is the most common form of PH, ultimately leading to right ventricular (RV) failure and contributing to morbidity and mortality in LHD patients. Pulmonary vascular remodeling further aggravates PH-LHD by increasing pulmonary vascular resistance (PVR). Yet, implantation of left ventricular assist devices or heart transplantation can normalize PVR in PH-LHD patients over time, suggesting that unloading of the pulmonary circulation reverses pulmonary vascular remodeling via physiological mechanisms that are not yet understood but may point to novel therapeutic strategies in PH. Here, we applied a recently established rat model of aortic banding/debanding to recapitulate this clinical scenario with the aim to identify drivers of reverse pulmonary vascular remodeling as putative novel therapeutic targets. Methods: Reverse vascular remodeling was induced in a rat model of PH-LHD by initial surgical aortic banding (AoB) followed after 3 weeks by surgical debanding (AoD) ( Sang et al., 2022 ). Reverse remodeling of pulmonary arteries (PA) and the RV was evaluated by hemodynamic assessment and (immuno-)histological analyses of lung and heart tissue samples. Candidate genes driving PA reverse remodeling were identified by bulk RNA sequencing of sham, AoB, and AoD PA samples. Candidate genes/pathways were functionally and mechanistically explored in primary PA smooth muscle cells (PASMC) isolated from sham and AoB rats by immunocytochemistry, proliferation, migration assays and Seahorse assays. Results: Hemodynamic assessment and histological analyses revealed normalization of pulmonary and RV hemodynamics and reversal of pulmonary vascular and RV wall remodeling in AoD vs. AoB rats. Immunostaining for Ki67 revealed reduced PASMC proliferation in PAs of AoD vs. AoB rats that was paralleled by a decrease in RV, wall thickness, width, and area of cardiomyocytes. RNA sequencing identified genes related to mitochondrial functions (TCA-cycle and respiratory electron transport, fatty acid oxidation) as gene clusters uniquely upregulated in AoD rats. Immunostaining for Tom20 revealed reduced mitochondrial content in PAs of AoB rats, but reconstitution in AoD. We next identified upregulation of two transcriptional regulators of mitochondrial biogenesis and dynamics in PAs of AoD rats, namely the transcriptional cofactor PGC1α (PPARγ-coactivator-1α) and the nuclear receptor ERRγ (estrogen-related receptor γ).Western blot revealed reduced protein expression of PGC1α and ERRγ in AoB PASMCs compared to sham PASMCs. The activation of PGC1α or ERRγ by ZLN005 or DY131, respectively, normalized mitochondrial morphology and ATP production, and inhibited proliferation and migration of AoB PASMCs. Conclusions: Surgical aortic debanding reverses lung vascular and RV remodeling in PH-LHD rats. Transcriptomic analyses and immunohistochemistry identified restoration of mitochondrial structure and function as putative mechanism of reverse remodeling, and PGC1α and ERRγ as potential drivers of this adaptation. The latter notion is supported by the finding that PGC1α and ERRγ agonists restore mitochondrial structure and function while inhibiting hyperproliferation in AoB PASMCs. As such, PGC1α and ERRγ emerge as putative therapeutic targets to induce reverse vascular remodeling in PH-LHD via restoration of mitochondrial homeostasis. Supported by grants from the German Center for Cardiovascular Research (DZHK), the German Research Foundation (DFG), and the Berlin Institute of Health (BIH). 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.