The present invention is based in part on the discovery that the upstream open reading frame (uORF) in the extended 5'-untranslated region (5'-UTR) argininosuccinate synthase (AS) mRNA species is functional, and when functional, limits overall AS expression as well as nitric oxide (NO) production. Thus, the extended 5'-UTR AS mRNA species is a mechanism for regulating AS expression and NO production, and provides a target for the treatment of pathophysiological conditions associated with vascular endothelial dysfunction and characterized by impairment of NO production, such as heart failure, hypertension, hypercholesterolemia, atherosclerosis, and diabetes.