Circulation. 2026 Jun 10. doi: 10.1161/CIRCULATIONAHA.125.066183. Online ahead of print.
ABSTRACT
BACKGROUND: Pulmonary hypertension (PH) is a progressive, life-threatening disease characterized primarily by pulmonary vascular remodeling in which endothelial dysfunction plays a vital role. However, the molecular factors contributing to this pathological process remain incompletely understood. Through proteomic analysis of hypoxia-treated human pulmonary artery endothelial cells, we identified serine hydroxymethyltransferase 2 (SHMT2) as a potential target in PH, but its role in disease pathogenesis and the underlying mechanisms remain unclear.
METHODS: The expression and function of SHMT2 were assessed in lung samples from patients with PH and in rodent PH models, including hypoxia-exposed mice and monocrotaline- or Sugen 5416/hypoxia-induced rats. Endothelial cell-specific SHMT2 loss and gain of function were achieved by conditional knockout and adeno-associated virus 9-mediated gene modulation. In vitro studies were performed in hypoxia-treated human pulmonary artery endothelial cells and HEK-293T cells. Virtual screening was used to identify a small-molecule inhibitor targeting the nonmetabolic function of SHMT2, and its therapeutic potential was further evaluated in rodent PH models.
RESULTS: SHMT2 was upregulated predominantly in pulmonary vascular endothelium of patients with PH and multiple rodent PH models. In vivo, endothelial cell-specific deletion of Shmt2 markedly attenuated pulmonary vascular remodeling and right ventricular dysfunction in PH mice, whereas endothelial cell-specific Shmt2 overexpression aggravated PH development. Consistently, adeno-associated virus 9-mediated endothelial Shmt2 knockdown alleviated PH phenotypes in rat models. Mechanistically, SHMT2 promoted hypoxia-induced endothelial barrier dysfunction mainly through a noncanonical function by blocking the K63-ubiquitin-mediated lysosomal degradation of ras homolog family member B (RhoB). Additional in vivo studies supported an important role of the endothelial SHMT2-RhoB axis in pulmonary vascular remodeling of PH. Through virtual screening, Namodenoson was identified as a small-molecule inhibitor targeting the SHMT2-RhoB pathway. In vivo, Namodenoson showed both preventive and therapeutic effects against PH.
CONCLUSIONS: This study highlights endothelial SHMT2 as an important contributor to PH pathogenesis and reveals a noncanonical SHMT2-RhoB pathway that promotes endothelial dysfunction. Targeting this pathway may represent a potential therapeutic strategy for PH.
PMID:42267432 | DOI:10.1161/CIRCULATIONAHA.125.066183