FIGURE 9.

Schematic of proposed mechanism: cardiac structure and function rely on the homeostatic interaction between EPO-EPOR and VEGF-VEGFR signaling. Top left panel: (1) In adult wildtype mice (EPO^fl/fl), the cardiomyocyte produces low levels of Epo at baseline (Figure 1). (2) Cardiomyocyte derived EPO (“EPO-C″) represses endothelial cell EPO (“EPO-E″) production in a paracrine fashion. (3) VEGF elicits paracrine stimulation of VEGFR on neighboring endothelial cells and cardiomyocytes, and activation of this pathway inhibits EPO-E production. The net outcome of these stimuli is reciprocal endothelial repression of EPO production. Top right panel: (1) In EPO-C null mice (EPO^Δ/Δ) EPO is successfully knocked out of the cardiomyocyte. (2) The lack of EPO produced by the cardiomyocytes releases the inhibition of EPO-EPOR by the endothelial cell in a paracrine fashion. (3) This leads to overproduction of EPO by the endothelial cell. (4) The overproduction of EPO positively feeds back and binds the EPOR₂ located on the cardiomyocyte (Wright et al., 2004). EPO binding to the EPOR₂ on the cardiomyocyte may induce cardiomyocyte-production of VEGF. (5) Increased VEGF-B-VEGFR-1 signaling, along with (6) additional unknown intermediate factors, increase myocyte hypertrophy, contractile function, and cardioprotection (Karpanen et al., 2008b; Zentilin et al., 2010; Kivelä et al., 2014; Lal et al., 2017). Bottom panel: (1) Axitinib, a pan-tyrosine kinase inhibitor, prevents downstream VEGF-VEGFR signaling. (2) VEGF-induced inhibition of EPO is interrupted, resulting in an increase in EPO-E and EPO-C production. The net outcome of VEGF-VEGFR inhibition is impaired cardiac function and bradycardia, despite increased EPO production. The mechanisms underlying these physiological consequences require future work.