Catalyzed by endothelial nitric oxide (NO) synthase (eNOS) activity, NO is a gaseous signaling molecule maintaining endothelial and cardiovascular homeostasis. Principally, NO regulates the contractility of vascular smooth muscle cells and permeability of endothelial cells in response to either biochemical or biomechanical cues. In the conventional outflow pathway of the eye, the smooth muscle-like trabecular meshwork (TM) cells and Schlemm's canal (SC) endothelium control aqueous humor outflow resistance, and therefore intraocular pressure (IOP). The mechanisms by which outflow resistance is regulated are complicated, but NO appears to be a key player as enhancement or inhibition of NO signaling dramatically affects outflow function; and polymorphisms in NOS3, the gene that encodes eNOS modifies the relation between various environmental exposures and glaucoma. Based upon a comprehensive review of past foundational studies, we present a model whereby NO controls a feedback signaling loop in the conventional outflow pathway that is sensitive to changes in IOP and its oscillations. Thus, upon IOP elevation, the outflow pathway tissues distend, and the SC lumen narrows resulting in increased SC endothelial shear stress and stretch. In response, SC cells upregulate the production of NO, relaxing neighboring TM cells and increasing permeability of SC's inner wall. These IOP-dependent changes in the outflow pathway tissues reduce the resistance to aqueous humor drainage and lower IOP, which, in turn, diminishes the biomechanical signaling on SC. Similar to cardiovascular pathogenesis, dysregulation of the eNOS/NO system leads to dysfunctional outflow regulation and ocular hypertension, eventually resulting in primary open-angle glaucoma.

由内皮一氧化氮 (NO) 合酶 (eNOS) 活性催化，NO 是一种气体信号分子，可维持内皮和心血管稳态。主要是，NO 响应生化或生物力学信号调节血管平滑肌细胞的收缩性和内皮细胞的通透性。在眼睛的常规流出通路中，平滑肌样小梁网 (TM) 细胞和施累姆氏管 (SC) 内皮控制房水流出阻力，从而控制眼压 (IOP)。调节流出阻力的机制很复杂，但 NO 似乎是一个关键因素，因为 NO 信号的增强或抑制会显着影响流出功能；和 NOS3 中的多态性，编码 eNOS 的基因改变了各种环境暴露与青光眼之间的关系。基于对过去基础研究的全面回顾，我们提出了一个模型，其中 NO 控制传统流出通路中的反馈信号回路，该通路对 IOP 的变化及其振荡敏感。因此，在 IOP 升高时，流出通路组织扩张，SC 管腔变窄，导致 SC 内皮剪切应力和拉伸增加。作为回应，SC 细胞上调 NO 的产生，放松邻近的 TM 细胞并增加 SC 内壁的渗透性。流出通路组织中的这些 IOP 依赖性变化降低了对房水引流的阻力并降低了 IOP，这反过来又减少了 SC 上的生物力学信号传导。类似于心血管的发病机制，