Gucy1a1 encodes one subunit of the soluble guanylyl cyclase (sGC) protein, a heterodimer formed with GUCY1B1. sGC is an effector enzyme of nitric oxide (NO), influencing vasoreactivity and platelet function, and is involved in pathways related to thrombotic processes, blood pressure regulation, and potentially tumor-associated processes [1,2,3]. Genetic models, like zebrafish models, can be used to study its functions [3].

In a zebrafish gucy1a1 mutant line generated by CRISPR-Cas9, a 4-bp deletion frameshift mutation led to reduced gucy1a1 expression. Blood flow parameters showed a significant increase in blood flow and linear velocity, especially in homozygotes. Co-morpholino downregulation of gucy1a1 and gucy1b1 also increased blood flow and linear velocity. The pharmacological sGC stimulator BAY41-2272 rescued impaired cGMP production in gucy1a1 ± mutant larvae [3]. In Ldlr -/- mice, functional loss of sGC in platelets contributed to atherosclerotic plaque formation, via increased in vivo leukocyte adhesion to atherosclerotic lesions. Supernatant from activated platelets lacking sGC promoted leukocyte adhesion to endothelial cells, and reduced platelet angiopoietin-1 release by sGC-depleted platelets enhanced leukocyte adhesion to ECs. Pharmacological sGC stimulation reduced leukocyte recruitment and atherosclerotic plaque formation [2].

In conclusion, Gucy1a1 is crucial for sGC-related functions in regulating blood flow and preventing atherosclerotic plaque formation. The use of gene-modified zebrafish and mouse models has provided valuable insights into the role of Gucy1a1 in these processes, which are relevant to cardiovascular disease research.