Protective role of endothelial nitric oxide synthase following pressure-induced insult to the optic nerve

Abstract

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In this paper we use the pig optic nerve, a typical central white matter tract, to study the time-dependent sequence of NOS isoform change following pressure elevation. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT TITLE: PROTECTIVE ROLE OF ENDOTHELIAL NITRIC OXIDE SYNTHASE FOLLOWING PRESSURE-INDUCED INSULT TO THE OPTIC NERVE AuthorsThe timing of NOS isoform change in relationship to structural and functional changes to axons and glial cells is also discussed. This study demonstrates that endothelial cell nitric oxide synthase (ecNOS), an enzyme that plays a protective role in the CNS, is up-regulated in a time-dependent manner after pressure elevation.ecNOS levels increase after axonal and astrocyte injury, suggesting that it might be a compensatory response that is initiated in an effort to preserve CNS function.Inducible NOS (iNOS) and neuronal NOS (nNOS), which are known to have a deleterious effect on the CNS, were not detected in this study. The increase in ecNOS demonstrated in this study is significantly different to the increase in iNOS and nNOS previously demonstrated following traumatic brain injury. Changes in ecNOS levels may therefore be important in the development of neuronal tolerance in the early stages of CNS diseases such as hydrocephalus. 3A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT IntroductionRaised intracranial pressure (ICP), which is commonly associated with traumatic brain injury (TBI) and hydrocephalus, can have a deleterious impact on central nervous system (CNS) structure and function (Prins et al. 1996;Sainte-Rose C 1996).Neuronal cytoskeleton disruption and axonal transport alteration, which are hallmarks of CNS injury, have been demonstrated in the early stages of both TBI and hydrocephalus (Chovanes et al. 1988;Aoyama et al. 2006;Kupina et al. 2003).However, the neuronal prognosis and long term neurological morbidity for each of these conditions is known to be vastly different. ICP control is the mainstay of A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPTIn this paper we report time-dependent NOS isoform changes following pressure elevation using optic nerves where axonal transport, cytoskeleton protein and astrocyte changes have been previously documented. Our experimental design has allowed us to correlate the sequence of neuronal and glial cell changes with individual NOS isoform changes following pressure elevation. By comparing changes between regions of absolute pressure increase and regions of pressure gradient increase we have also been able to determine the influence of important phy...

Characterization of nitric oxide signaling pathways in the mouse retina

“…The specificity of the nNOS antisera used in this study was previously established with Western blots (Giove et al, 2009). The specificity of the monoclonal antisera directed against eNOS has been characterized in retina by using both immunocytochemistry and Western blots (Balaratnasingam et al, 2009). The characteristic labeling in horizontal cells seen with the calbindin antisera and the labeling of rod bipolar cells seen with the PKCa antisera was identical to that previously described for the C57/Bl6J mouse retina (Haverkamp and Wassle, 2000).…”

Microvascular Density Is Associated With Retinal Ganglion Cell Axonal Volume in the Laminar Compartments of the Human Optic Nerve Head

“…T he human optic nerve head (ONH) is composed of approximately 1.2 million retinal ganglion cell (RGC) axons and is one of the most metabolically active sites in the central nervous system. 1 The energy demands of RGC axons along the course of the ONH are not uniform as evidenced by the marked variation in mitochondrial enzymes, 2 cytoskeletal proteins, [3][4][5] myelin proteins, 6,7 astrocytes, 8,9 and nitric oxide synthase systems 10 between laminar regions. The highly compartmentalized nature of RGCs 11 and the marked heterogeneity in energy supply/demand relationships between laminar compartments are proposed to be an important reason why certain sites within the ONH are more vulnerable to injury and disease than others.…”

Morphometric Characteristics of Central Retinal Artery and Vein Endothelium in the Normal Human Optic Nerve Head

“…2,3 In vivo optic nerve measurements performed in our laboratory and other centers have demonstrated the presence of a significant pressure gradient at the lamina cribrosa, which is consequent to the decrease in tissue pressures between prelaminar and retrolaminar regions of the optic nerve head. 4 -7 Previous reports, together with histologic studies also performed in our laboratory, have revealed important correlations between the change in translaminar tissue pressure and the distribution of neuronal cytoskeleton proteins, 8 mitochondria, 9,10 nitric oxide synthase enzymes, 11 and axonal transport processes, [12][13][14] suggesting that optic nerve tissue is cyto-architecturally adapted to the laminar environment. It is unknown if anatomical and physiological variations within the human optic nerve head have a similar influence on regional CRA and CRV endothelial characteristics; however, this knowledge would be useful for improving our understanding of pathogenic mechanisms underlying ocular vascular diseases.…”