Divergent roles of endothelial and red blood cell nitric oxide synthase in regulating cardiovascular function during anemia

Background

Red blood cells (RBCs) express functional endothelial nitric oxide synthase (eNOS), which regulates blood pressure (BP) independently of eNOS in endothelial cells (ECs) and provides cardioprotection during acute myocardial infarction (AMI). The functional role of RBC- and EC- eNOS in anemia remains unknown. This study evaluated the effects of RBC- or EC-specific eNOS deletion on hemodynamics and cardiac function in blood loss anemia.

Methods

and resultsAnemia was induced in EC- or RBC-specific eNOS knockout (KO) mice and their respective controls. In vivo flow-mediated dilation (FMD) was preserved in RBC-eNOS-KO mice under both baseline and anemic conditions but was impaired in EC-eNOS-KO mice compared to their respective controls. Wire myograph analysis of aortic rings showed preserved endothelium-dependent relaxation (EDR) in anemic RBC-eNOS-KO mice, while EDR was abolished in anemic EC-eNOS-KO mice relative to controls. Miller catheter BP measurements revealed elevated systolic and diastolic BP in EC-eNOS-KO mice under both baseline and anemic conditions. Both systolic and diastolic BP were increased in RBC-eNOS-KO mice compared to controls, whereas these parameters remained unchanged in anemic RBC-eNOS-KO mice compared to their respective controls. Echocardiography demonstrated preserved cardiac function across all genotypes at baseline, 3 days post-anemia, and 24 h post-reperfused AMI. However, infarct size was significantly increased in anemic RBC-eNOS-KO mice compared to controls.

Conclusions

Anemia mitigates the BP elevation caused by RBC-eNOS deletion, while hypertension persists in the absence of endothelial eNOS, highlighting vascular eNOS as the predominant regulator of BP under anemic conditions. RBC-eNOS limits infarct size under anemic conditions.