Role of nitric oxide in murine conventional outflow physiology

Chang, Jason Y. H.; Stamer, W. Daniel; Bertrand, Jacques; Read, A. Thomas; Marando, Catherine M.; Ethier, C. Ross; Overby, Darryl R.

doi:10.1152/ajpcell.00347.2014

Cited by 86 publications

(94 citation statements)

References 64 publications

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“…5a–c, L-NAME significantly reduced outflow facility by 45% in Cav-1 −/− eyes compared to vehicle-perfused eyes similar to recently published results29. Importantly, L-NAME reduced outflow facility in wildtype control eyes by only 26%, consistent with our previous report37. These results demonstrate enhanced sensitivity of Cav-1 −/− eyes to eNOS inhibition and that eNOS hyperactivity secondary to Cav-1 loss may partially rescue outflow pathology.…”

Section: Resultssupporting

confidence: 91%

Caveolin-1 modulates intraocular pressure: implications for caveolae mechanoprotection in glaucoma

Elliott

Ashpole

et al. 2016

Sci Rep

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Polymorphisms in the CAV1/2 genes that encode signature proteins of caveolae are associated with glaucoma, the second leading cause of blindness worldwide, and with its major risk factor, intraocular pressure (IOP). We hypothesized that caveolin-1 (Cav-1) participates in IOP maintenance via modulation of aqueous humor drainage from the eye. We localize caveolae proteins to human and murine conventional drainage tissues and show that caveolae respond to mechanical stimulation. We show that Cav-1-deficient (Cav-1−/−) mice display ocular hypertension explained by reduced pressure-dependent drainage of aqueous humor. Cav-1 deficiency results in loss of caveolae in the Schlemm’s canal (SC) and trabecular meshwork. However, their absence did not appear to impact development nor adult form of the conventional outflow tissues according to rigorous quantitative ultrastructural analyses, but did affect cell and tissue behavior. Thus, when IOP is experimentally elevated, cells of the Cav-1−/− outflow tissues are more susceptible to plasma membrane rupture indicating that caveolae play a role in mechanoprotection. Additionally, aqueous drainage from Cav-1−/− eyes was more sensitive to nitric oxide (NO) synthase inhibition than controls, suggesting that excess NO partially compensates for outflow pathway dysfunction. These results provide a functional link between a glaucoma risk gene and glaucoma-relevant pathophysiology.

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Section: Resultssupporting

confidence: 91%

Caveolin-1 modulates intraocular pressure: implications for caveolae mechanoprotection in glaucoma

Elliott

Ashpole

et al. 2016

Sci Rep

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“…As a vessel-like endothelial layer, supplement of endogenous NO in Schlemm's canal decreased the volume of endothelial cells (Ellis et al, 2010) and increased outflow facility (Chang et al, 2015). A recently identified cytokine signaling pathway may provide additional gene therapy targets that are downstream of the TM (Alvarado et al, 2015).…”

Section: Current Challenges and Future Directionsmentioning

confidence: 99%

Gene transfer to the outflow tract

Dang

Loewen

Parikh

et al. 2017

Experimental Eye Research

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Elevated intraocular pressure is the primary cause of open angle glaucoma. Outflow resistance exists within the trabecular meshwork but also at the level of Schlemm's canal and further downstream within the outflow system. Viral vectors allow to take advantage of naturally evolved, highly efficient mechanisms of gene transfer, a process that is termed transduction. They can be produced at biosafety level 2 in the lab using protocols that have evolved considerably over the last 15 to 20 years. Applied by an intracameral bolus, vectors follow conventional as well as uveoscleral outflow pathways. They may affect other structures in the anterior chamber depending on their transduction kinetics which can vary among species when using the same vector. Not all vectors can express long-term, a desirable feature to address the chronicity of glaucoma. Vectors that integrate into the genome of the target cell can achieve transgene function for the life of the transduced cell but are mutagenic by definition. The most prominent long-term expressing vector systems are based on lentiviruses that are derived from HIV, FIV, or EIAV. Safety considerations make non-primate lentiviral vector systems easier to work with as they are not derived from human pathogens. Non-integrating vectors are subject to degradation and attritional dilution during cell division. Lentiviral vectors have to integrate in order to express while adeno-associated viral vectors (AAV) often persist as intracellular concatemers but may also integrate. Adeno- and herpes viral vectors do not integrate and earlier generation systems might be relatively immunogenic. Nonviral methods of gene transfer are termed transfection with few restrictions of transgene size and type but often a much less efficient gene transfer that is also short-lived. Traditional gene transfer delivers exons while some vectors (lentiviral, herpes and adenoviral) allow transfer of entire genes that include introns. Recent insights have highlighted the role of non-coding RNA, most prominently, siRNA, miRNA and lncRNA. SiRNA is highly specific, miRNA is less specific, while lncRNA uses highly complex mechanisms that involve secondary structures and intergenic, intronic, overlapping, antisense, and bidirectional location. Several promising preclinical studies have targeted the RhoA or the prostaglandin pathway or modified the extracellular matrix. TGF-β and glaucoma myocilin mutants have been transduced to elevate the intraocular pressure in glaucoma models. Cell based therapies have started to show first promise. Past approaches have focused on the trabecular meshwork and the inner wall of Schlemm's canal while new strategies are concerned with modification of outflow tract elements that are downstream of the trabecular meshwork.

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“…This radical affects an early step in the replication cycle of influenza viruses and NO has been shown to severely impair the replication of influenza A and B viruses 11. In the outflow physiology, NO has been reported to contribute to the physiological regulation of aqueous humor outflow and to lower intraocular pressure in various animal models and human patients 5, 12, 13, 14, 15…”

Section: Introductionmentioning

confidence: 99%

Progress and Promise of Nitric Oxide‐Releasing Platforms

2018

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Nitric oxide (NO) is a highly potent radical with a wide spectrum of physiological activities. Depending on the concentration, it can enhance endothelial cell proliferation in a growth factor‐free medium, mediate angiogenesis, accelerate wound healing, but may also lead to tumor progression or induce inflammation. Due to its multifaceted role, NO must be administered at a right dose and at the specific site. Many efforts have focused on developing NO‐releasing biomaterials; however, NO short half‐life in human tissues only allows this molecule to diffuse over short distances, and significant challenges remain before the full potential of NO can be realized. Here, an overview of platforms that are engineered to release NO via catalytic or noncatalytic approaches is presented, with a specific emphasis on progress reported in the past five years. A number of NO donors, natural enzymes, and enzyme mimics are highlighted, and recent promising developments of NO‐releasing scaffolds, particles, and films are presented. In particular, key parameters of NO delivery are discussed: 1) NO payload, 2) maximum NO flux, 3) NO release half‐life, 4) time required to reach maximum flux, and 5) duration of NO release. Advantages and drawbacks are reviewed, and possible further developments are suggested.

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Role of nitric oxide in murine conventional outflow physiology

Cited by 86 publications

References 64 publications

Caveolin-1 modulates intraocular pressure: implications for caveolae mechanoprotection in glaucoma

Caveolin-1 modulates intraocular pressure: implications for caveolae mechanoprotection in glaucoma

Gene transfer to the outflow tract

Progress and Promise of Nitric Oxide‐Releasing Platforms

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