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The vital role for nitric oxide in intraocular pressure homeostasis.

ABSTRACT: 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.

SUBMITTER: Reina-Torres E

PROVIDER: S-EPMC8160027 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Aims: Cardiomyocyte-specific nitric oxide synthase 3 (NOS3) overexpression reduces left ventricular (LV) remodelling after myocardial infarction in mice, but its effect on sustained LV pressure-overload remains incompletely understood. We investigated LV structural and functional adaptation to elevated afterload in mice with cardiomyocyte-restricted NOS3 overexpression (NOS3TG) and wild type littermates (WT). Methods and Results: Hemodynamic indices, cardiac hypertrophy and interstitial fibrosis were measured 10 weeks after transverse aortic constriction (TAC). After 10 weeks TAC, NOS3TG had better preserved systolic function (maximum rates of pressure development normalized to maximal pressure 77Â±6 versus 65Â±2 ms-1, P=0.05), reduced heart weight-body weight ratio (HW/BW, 5.0Â±0.3 versus 5.8Â±0.1, P<0.05), and cardiomyocyte width than WT (14.9Â±0.4 vs 16.7Â±0.2 ?m, P<0.05). After 10 weeks TAC, a 44k cDNA chip-based microarray analysis was validated using real time PCR and revealed significantly altered expression pattern of genes involved in cellular growth, matrix remodelling, and inflammation between genotypes. Conclusions: Cardiomyocyte-restricted NOS3 overexpression attenuates TAC-induced hypertrophy via autocrine inhibition of cardiomyocyte cell growth, but does not mitigate myocardial fibrosis. The subsequent diastolic dysfunction suggests that inhibition of matrix producing cells during hypertrophic stress is necessary to prevent functional and structural deterioration of the pressure-overloaded heart. Left ventricular mRNA expression profiles were compared between alpha-myosin heavy chain driven nitric oxide synthase 3 (alpha-MHC-NOS3) transgenic and wild type (WT) littermate mice at baseline and 10 weeks after transversal aortic constrcition-induced pressure-overload. Biological repeats: n=4, two males and two females, for each group and condition. Transgenic mice were backcrossed for seven generations (F7) to a C57Bl/6 N background and age and weight matched animals were used for microarray experiments.

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The vital role for nitric oxide in intraocular pressure homeostasis.

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