The role of NO/sGC signaling in erythropoiesis: Lessons from erythroid-specific knock-out and knock-in mice

https://doi.org/10.1007/s00392-024-02526-y

Sophia K. Heuser (Düsseldorf)1, A. LoBue (Düsseldorf)1, J. Li (Düsseldorf)1, R.-P. Cadeddu (Düsseldorf)2, Lundberg (Stockholm)3, E. Mergia (Bochum)4, U. Germing (Düsseldorf)2, M. Cortese-Krott (Düsseldorf)1

1Universitätsklinikum Düsseldorf Klinik für Kardiologie, Pneumologie und Angiologie Düsseldorf, Deutschland; 2Universitätsklinikum Düsseldorf Klinik für Hämatologie, Onkologie und Immunologie Düsseldorf, Deutschland; 3Karolinska Institutet Department of Physiology and Pharmacology Stockholm, Schweden; 4Marien Hospital Herne - Universitätsklinikum der Ruhr-Universität Bochum Institut für Pharmakologie und Toxikologie Bochum, Deutschland

 

Vericiguat is a specific and potent activator of the nitric oxide (NO) receptor soluble guanylyl cyclase (sGC). In the VICTORIA trial (Vericiguat Global Study in Patients with Heart Failure with Reduced Ejection Fraction), anemia occurred more often in patients treated with vericiguat (7.6%) than with placebo (5.7%). This results is surprising because NO/ soluble guanylyl cyclase (sGC) signaling pathway in human erythroid cells has been proposed to drive the expression of γ-globin and control erythropoiesis, but its role in vivo has not yet been demonstrated. To veryfy the role of sGC in erythropoiesis, we generated erythroid cell-specific erythroid-specific sGC KO mice, using the loxP/Cre recombinase gene targeting approach. We confirmed the specificity of gene targeting by analyzing erythroid cell-specific DNA recombination, target protein expression, and/or activity using qPCR, western blotting, ELISA, and enzymatic assays. To analyze changes in the hematopoietic phenotype, we analyzed the peripheral blood cell and reticulocyte counts. In the bone marrow and spleen of the mice, we analyzed cellular composition, quantified stage-specific cell differentiation by flow cytometry, and performed a functional colony assay. Moreover, we determined the vascular function, systemic hemodynamics, and NO metabolites. We found that RBC sGC KO mice show disrupted erythropoiesis in the bone marrow and a compensatory stress erythropietic response in the spleen, characterized by spelomegalie and presence of progenitor erythroid cells. These results show that in sGC play a major role in erythroid differentiation in vivo and indicate that it is unlikely that Vericiguat induced anemia was not due to specific GC activation in bone marrow cells of patients with heart failure.

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