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Editors Selection IGR 16-4

Basic Research: IOP regulators

Paul Kaufman

Comment by Paul Kaufman on:

48121 eNOS, a Pressure-Dependent Regulator of Intraocular Pressure, Stamer W; Lei Y; Boussommier-Calleja A et al., Investigative Ophthalmology and Visual Science, 2011; 52: 9438-9444


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The manuscript by Stamer et al. (1729) reports that eNOS knock-in transgenic mice have lower spontaneous IOP and higher pressure- dependent drainage of aqueous humor, presumably representing conventional (trabecular meshwork) outflow facility, than their wild-type counterparts. Further, the NOS inhibitor L-NAME normalized pressure-dependent drainage in the knock-in animals, while at IOP > 35 mmHg the pressure- flow relationship (i.e., the conventional outflow facility) in the wild-type mice increased and was indistinguishable from that continuously present in the eNOS knock-in mice at lower IOP. These beautifully conceived and impeccably executed experiments by a very strong multi-institutional/multi-national team establish several important concepts:

  • Nitric oxide (NO) serves as a mediator for increasing trabecular meshwork (conventional, pressure-dependent) outflow facility;
  • The NO-facility relationship can be manipulated both genetically and pharmacologically;
  • Mechanical distension of the trabecular meshwork triggers an NO-mediated increase in facility, suggesting trabecular meshwork mechano-sensitivity as a homeostatic mechanism mediated at least in part by NO to maintain a normal outflow facility and IOP.
This constellation of data and interpretation is consistent with studies showing that interference with trabecular meshwork cellular contractility, and cell-cell or cell-extracellular matrix adhesion, whether by inhibiting the rho kinase or myosin light-chain kinase cascades or by disrupting action microfilaments (whether by direct disruption or inhibition of their assembly), will increase outflow facility.1 This process also may reflect a mechanical homeostatic regulation of outflow facility in response to mechanical deformation of the trabecular meshwork caused by stress-strain, shear-stress and other pressure-related phenomena, or in response to biochemical, hormonal or metabolic alterations in the surrounding milieu.

Thus the trabecular meshwork appears to be a self-coordinated functioning organ, aligned in some unknown way in a homeostatic drive toward a 'normal' IOP. The cytoskeleton/contractility mechanisms may be the efferent 'execution' arm of the reflexive/regulatory mechanism; their arrangement governs the final facility. The eNOS/NO system is a signal/transduction arm that mediates response to the stressors.

The existence of the TM as a responsive self-aware, self-regulating tissue/organ is supported. Concrete evidence of a NO based signal transduction mechanism as a crucial part of that system is provided

The actual 'sensors' to stress/strain/distension etc. within the trabecular meshwork are largely unknown, although some mechanosensory elements have been described in the anterior and posterior tendons of the ciliary muscle in primates, and in the muscle apex (the latter perhaps more related to the fine control of accommodation than to regulation of outflow facility).2-4

The Stamer article supports the existence of the TM as a responsive self-aware, self-regulating tissue/organ, and provides concrete evidence of a NO-based signal transduction mechanism as a crucial part of that system. Caveats about extrapolation from mice to primate/ human systems, and to a role in pathophysiology or treatment of POAG notwithstanding, this is a beautifully conceived, executed, interpreted and important piece of work.

References

  1. Tian B, Gabelt BT, Geiger B, Kaufman PL. The role of the actomyosin system in regulating trabecular fluid outflow. Exp Eye Res 2009; 88: 713-717.
  2. Tamm ER. The trabecular meshwork outflow pathways: structural and functional aspects. Exp Eye Res 2009; 88: 648-655.
  3. Flügel-Koch C, Neuhuber WL, Kaufman PL, Lütjen-Drecoll E. Morphologic indication for proprioception in the human ciliary muscle. Invest Ophthalmol Vis Sci 2009; 50: 5529-5536.
  4. Selbach JM, Gottanka J, Wittmann M, Lütjen-Drecoll E. Efferent and afferent innervation of primate trabecular meshwork and scleral spur. Invest Ophthalmol Vis Sci 2000; 41: 2184-2191.


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