Nitric oxide (NO) is an important signaling molecule in the cardiovascular system. Reduced bioavailability of NO results in debilitated signaling, which contributes to the pathogenesis of cardiometabolic disorders. However, the alterations in signaling under NO deficiency remain mostly unknown. To gain an appreciation of the signaling landscapes during NO deficiency we combined genetics and proteomics to quantify changes in the heart proteome, phosphoproteome, and S-nitrosocysteine proteome in mice lacking each of the nitric oxide synthases, NOS1, NOS2, and NOS3, mice lacking all three enzymes (tNOS), or the alpha 1-regulatory subunit of the soluble guanylate cyclase (sGCα1). Modest changes, less than 1% in the proteome and 4% in the phosphoproteome were quantified in single NOS gene or sGCα1 deletion mouse hearts indicating sufficient biological compensation. In contrast, the absence of a single NOS gene reduced the number of S-nitrosylated proteins by 80%, 57%, and 35% in NOS3, NOS1, and NOS2 null mice respectively. The profound deficit of S-nitrosylated proteins in the NOS3 null mice was localized in metabolic pathways, which may explain the metabolic dysregulation that develops in these mice. A 21% remodeling of the proteome and 9% of the phosphoproteome was quantified in the tNOS null mice. We quantified changes in the levels and regulation of integral kinases indicating an adaptive rewiring of signaling to secure essential functions such as contraction and metabolism in the tNOS null mice. The data revealed the emergence of enhanced mitogen-activated-kinases Mapk3/Mapk1 signaling documented by increased phosphorylation of these two kinases and their downstream targets in the sGCα1 and tNOS null mice. These data highlight that adaptive compensation of signaling prevents overt phenotypes during NO signaling deficits, whereas maladaptive signaling via Mapk3/Mapk1 may promote cardiac dysfunction and pathological cardiomyopathy that progressively develops in the tNOS null mice.