{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The α‐subunit of soluble guanylate cyclase—encoded by the GUCY1A1 gene (often referenced in the literature as the homologous GUCY1A3)—is the central sensor for nitric oxide (NO) that catalyzes the formation of cyclic guanosine monophosphate (cGMP). cGMP is a critical second messenger that governs vascular smooth muscle relaxation, modulates vascular tone and remodeling, and influences platelet aggregation. Multiple studies have demonstrated that genetic alterations or reduced expression of this subunit can disrupt NO signaling and thereby contribute to several cardiovascular pathologies, including moyamoya disease, hypertension, coronary artery disease, and stroke."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In animal models, loss or inhibition of the α‐subunit has been shown to prevent vascular smooth muscle cells from undergoing a phenotypic switch toward a synthetic state, thereby exerting an atheroprotective effect."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In parallel, rare coding variants that impair cGMP production can be functionally rescued by small‐molecule stimulators, underscoring the therapeutic potential of targeting this pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, specific variants in GUCY1A1 have been associated with phenotypic differences that modify platelet reactivity and clinical response to antiplatelet therapy, as well as protective influences in hypoxia‐induced pulmonary hypertension."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}, {"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Biochemical analyses further reveal that the basal activity of the enzyme can be enhanced by bioactive lipid molecules—such as lysolecithin—in cellular membranes, suggesting that lipid composition may modulate sGC activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " In addition, cross‐talk with other pathways has been documented; for example, in liver tumorigenesis, stabilizing interactions mediated by proteins such as TRIB2 help maintain GUCY1A1 stability, linking altered NO–cGMP signaling to metabolic dysregulation under high‐glucose conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings illuminate the multifaceted role of the GUCY1A1 gene product as a key regulator of NO signaling that not only governs vascular homeostasis but also influences platelet function and cellular responses in various disease contexts.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Dominique Hervé, Anne Philippi, Reda Belbouab, et al. 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