Schematic of CYB5R3 protein expression in pulmonary arterial SMCs and its effect on pulmonary artery vascular tone. Under normal conditions CYB5R3 in VSM regulates the redox state of sGC heme iron, maintaining sGC in its NO-sensitive reduced form (Fe²⁺), whereby signaling for cGMP production occurs and mediates vessel relaxation for low pulmonary vascular resistance. In SCD, CYB5R3 protein expression in VSM is relatively low and sGC heme iron oxidation (Fe³⁺) is high due to chronic hemolytic and oxidative stress. The result is “resistance” to NO signaling for cGMP production. This pathology produces a constricted pulmonary arterial phenotype, in which high vascular resistance increases pressure to drive pulmonary arterial hypertension and hyperplasia.