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: , 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.
Signoretti et al. (Tue,) studied this question.