Numerous experiments have shown that endothelial DHFR deficiency leads to decreased BH4 and eNOS uncoupling in many cardiovascular diseases, including hypertension, aortic aneurysm, and diabetic vascular complications (Gao et al., 2012; Youn et al., 2012; Li et al., 2019). The gene discussed is NOS3; the disease is cardiovascular disorder.