Endothelial Baf60c Alleviates Hyperoxia-Induced BPD-Associated Pulmonary Hypertension Through Smarcc2 and PI3K-Akt-mTOR Signaling
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BACKGROUND
Bronchopulmonary dysplasia–associated pulmonary hypertension (BPD-PH) complicates prematurity and carries substantial morbidity in extremely preterm infants. Pulmonary microvascular endothelial cell (PMVEC) dysfunction promotes capillary rarefaction and vascular remodeling, but epigenetic mechanisms after neonatal hyperoxia are poorly defined. Baf60c (SMARCD3), a SWI/SNF subunit supporting vascular homeostasis, and Smarcc2 (BAF170), a PBAF scaffold subunit linked to proliferative signaling, have not been studied together in BPD-PH.
METHODS
Neonatal C57BL/6 mice were exposed to 85% oxygen for 14 days. Right ventricular systolic pressure (RVSP), right ventricular hypertrophy, lung weight index, and pulmonary histopathology were assessed; PMVEC proliferation, migration, and invasion were measured. Transcriptome sequencing with GO/KEGG analyses, siRNA knockdown, LY294002 inhibition, coimmunoprecipitation, and Western blotting mapped the Baf60c–Smarcc2–PI3K-Akt-mTOR axis. A Tie1-driven, lung-tropic adeno-associated virus delivered by superficial facial vein injection at postnatal day 1 enabled PMVEC-specific Baf60c overexpression.
RESULTS
Hyperoxia increased RVSP, right ventricular hypertrophy, and lung weight index, impaired alveolarization, reduced capillary density, and promoted arteriolar remodeling. PMVEC function was impaired, with PI3K-Akt pathway enrichment and suppressed signaling. Hyperoxia decreased Baf60c and increased Smarcc2. Baf60c knockdown upregulated Smarcc2, suppressed PI3K-Akt-mTOR, and phenocopied hyperoxia; Smarcc2 knockdown had opposite effects. Baf60c bound Smarcc2 but not PI3K. PMVEC-specific Baf60c overexpression attenuated pulmonary hypertension and right ventricular hypertrophy and partially improved alveolar and microvascular injury.
CONCLUSIONS
Hyperoxia-induced BPD-PH is associated with reduced Baf60c, increased Smarcc2, and suppressed PI3K-Akt-mTOR signaling in PMVECs. Baf60c may indirectly regulate this pathway through Smarcc2. Endothelial Baf60c is a potential therapeutic target in BPD-PH.
Novelty and Relevance
What Is New?
A neonatal hyperoxia BPD-PH model was characterized with adverse hemodynamic and pulmonary vascular endpoints together with PMVEC functional impairment. Hyperoxia downregulates Baf60c, upregulates Smarcc2, and suppresses PI3K-Akt-mTOR signaling in PMVECs. Baf60c interacts with Smarcc2 without direct PI3K binding. PMVEC-specific Baf60c overexpression via superficial facial vein AAV delivery ameliorates pulmonary hypertension.
What Is Relevant?
BPD-PH is a developmental pulmonary hypertension phenotype in which pulmonary vascular resistance and right ventricular load are measurable with RVSP and Fulton index, consistent with Group 3 PH biology. SWI/SNF-mediated chromatin remodeling in pulmonary endothelium may link neonatal oxygen injury to impaired angiogenic endothelial function.
Clinical/Pathophysiological Implications?
Endothelial Baf60c deficiency may contribute to pulmonary vascular rarefaction after neonatal hyperoxia. Restoring endothelial Baf60c may improve pulmonary hemodynamics in BPD-PH, although structural lung injury may be only partially reversible.
