Heme-related generation of ROS decreases availability and or activation of soluble guanylyl cyclase or its regulators such as cytochrome b5 reductase 3 (CYB5R3), which can result in poor vasodilation of pulmonary vasculature, increasing the risk of pulmonary hypertension [55,56]. This evidence concerns the gene CYB5R3 and pulmonary arterial hypertension.