VEGFR-2 blocker induces pulmonary vascular disease in rats with CRISPR-edited human non-deficient G6PD polymorphism: role of 3D genomic modifications and DNA methylation

  • Br J Pharmacol. 2026 May 5. doi: 10.1111/bph.70452.
Christina Signoretti  1 ,  Shun Matsumura  1 ,  Jaser Doja  2 ,  Samuel Fatehi  1 ,  Comfort Williams  1 ,  Melinee D'silva  1 ,  Francesca Cendali  3 ,  Monika Dzieciatkowska  3 ,  Angelo D'Alessandro  3 ,  Gregg M Lanier  4 ,  Sachin A Gupte  1
Affiliations
  • 1. Department of Pharmacology, New York Medical College, Valhalla, New York, USA.
  • 2. Department of Medicine, Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
  • 3. Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
  • 4. Department of Cardiology, Heart and Vascular Institute, Westchester Medical Center, Valhalla, New York, USA.
PMID: 42083756 DOI: 10.1111/bph.70452
Abstract

Background and purpose: Vascular endothelial growth factor inhibitors (VEGFIs) and receptor (VEGFR) blockers are a standard-of-care treatment for Cancer, but they can induce pulmonary vascular disease (PVD) in some patients. Moreover, patients with certain polymorphisms in glucose-6-phosphate dehydrogenase (G6PD) are more susceptible to PVD. Therefore, we sought to determine the potential mechanisms that contribute to VEGFI-induced PVD in wild-type rats and in CRISPR-engineered rats with a non-deficient (N126D) and a deficient (S188F) G6PD polymorphism.

Experimental approach: We treated rats with SUGEN5416 (SU; semaxanib 20 mg·kg-1, s.c.) a VEGFR-2 blocker and determined right ventricular pressure. We performed histology and multiple omics approaches to determine the mechanism of SU-induced PVD.

Key results: SU increased right ventricular pressure in rats with a non-deficient (N126D) but not a deficient (S188F) glucose-6-phosphate dehydrogenase G6PD polymorphism. In addition, we uncovered that differences in the organization of the 3D genome and expression of genes encoding DNA and histone demethylases, cancer-related proteins, plasminogen activator inhibitor-1 (PAI-1) and inflammatory cytokines/chemokines (interleukin-1β [IL-1β] and CCL5) between the G6PD variants contributed to the disparate effects of VEGFR-2 blockade. For instance, VEGFR-2 blocker-induced expression of PAI-1 correlated positively with PVD in patients and evoked migration of pulmonary arterial smooth muscle cells.

Conclusion and implications: This suggests that our findings reflect a heretofore unknown connection between G6PD polymorphisms and the 3D genomic organization that controls VEGFR blocker-induced expression of DNA/histone demethylases. Potential effects include up-regulation of genes encoding proteins, which evoke cell migration and inflammation within the lungs and contribute to the pathogenesis of PVD.

Keywords
2‐hydroxyglutarate; epigenetics; hypertension; inflammation; lung; metabolic reprogramming; smooth muscle cell.
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