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Review
. 2022 Feb 1;63(2):12.
doi: 10.1167/iovs.63.2.12.

Consensus Recommendation for Mouse Models of Ocular Hypertension to Study Aqueous Humor Outflow and Its Mechanisms

Colleen M McDowell  1 , Krishnakumar Kizhatil  2 , Michael H Elliott  3 , Darryl R Overby  4 , Joseph van Batenburg-Sherwood  4 , J Cameron Millar  5 , Markus H Kuehn  6 , Gulab Zode  5 , Ted S Acott  7 , Michael G Anderson  8 , Sanjoy K Bhattacharya  9 , Jacques A Bertrand  10 , Terete Borras  11 , Diane E Bovenkamp  12 , Lin Cheng  13 , John Danias  14 , Michael Lucio De Ieso  15 , Yiqin Du  16 , Jennifer A Faralli  17 , Rudolf Fuchshofer  18 , Preethi S Ganapathy  19 , Haiyan Gong  20 , Samuel Herberg  19 , Humberto Hernandez  21 , Peter Humphries  22 , Simon W M John  23 , Paul L Kaufman  1 , Kate E Keller  24 , Mary J Kelley  25 , Ruth A Kelly  26 , David Krizaj  27 , Ajay Kumar  16 , Brian C Leonard  28 , Raquel L Lieberman  29 , Paloma Liton  30 , Yutao Liu  31 , Katy C Liu  32 , Navita N Lopez  33 , Weiming Mao  34 , Timur Mavlyutov  1 , Fiona McDonnell  32 , Gillian J McLellan  35 , Philip Mzyk  1 , Andrews Nartey  36 , Louis R Pasquale  37 , Gaurang C Patel  38 , Padmanabhan P Pattabiraman  34 , Donna M Peters  17 , Vijaykrishna Raghunathan  36 , Ponugoti Vasantha Rao  39 , Naga Rayana  34 , Urmimala Raychaudhuri  40 , Ester Reina-Torres  10 , Ruiyi Ren  20 , Douglas Rhee  41 , Uttio Roy Chowdhury  42 , John R Samples  43 , E Griffen Samples  44 , Najam Sharif  45 , Joel S Schuman  46 , Val C Sheffield  47 , Cooper H Stevenson  5 , Avinash Soundararajan  34 , Preeti Subramanian  12 , Chenna Kesavulu Sugali  34 , Yang Sun  48 , Carol B Toris  49 , Karen Y Torrejon  50 , Amir Vahabikashi  51 , Janice A Vranka  52 , Ting Wang  34 , Colin E Willoughby  53 , Chen Xin  54 , Hongmin Yun  55 , Hao F Zhang  56 , Michael P Fautsch  56 , Ernst R Tamm  57 , Abbot F Clark  58 , C Ross Ethier  59 , W Daniel Stamer  60
Affiliations
Review

Consensus Recommendation for Mouse Models of Ocular Hypertension to Study Aqueous Humor Outflow and Its Mechanisms

Colleen M McDowell et al. Invest Ophthalmol Vis Sci. .

Abstract

Due to their similarities in anatomy, physiology, and pharmacology to humans, mice are a valuable model system to study the generation and mechanisms modulating conventional outflow resistance and thus intraocular pressure. In addition, mouse models are critical for understanding the complex nature of conventional outflow homeostasis and dysfunction that results in ocular hypertension. In this review, we describe a set of minimum acceptable standards for developing, characterizing, and utilizing mouse models of open-angle ocular hypertension. We expect that this set of standard practices will increase scientific rigor when using mouse models and will better enable researchers to replicate and build upon previous findings.

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Conflict of interest statement

Disclosure: C.M. McDowell, None; K. Kizhatil, None; M.H. Elliott, None; D.R. Overby, None; J. van Batenburg-Sherwood, iPerfusion (C); J.C. Millar, None; M.H. Kuehn, None; G. Zode, None; T.S. Acott, None; M.G. Anderson, None; S.K. Bhattacharya, None; J.A. Bertrand, None; T. Borras, None; D.E. Bovenkamp, None; L. Cheng, None; J. Danias, None; M.L. De Ieso, None; Y. Du, None; J.A. Faralli, None; R. Fuchshofer, None; P.S. Ganapathy, None; H. Gong, None; S. Herberg, None; H. Hernandez, None; P. Humphries, None; S.W.M. John, None; P.L. Kaufman, None; K.E. Keller, None; M.J. Kelley, None; R.A. Kelly, None; D. Krizaj, None; A. Kumar, None; B.C. Leonard, None; R.L. Lieberman, None; P. Liton, None; Y. Liu, None; K.C. Liu, None; N.N. Lopez, None; W. Mao, None; T. Mavlyutov, None; F. McDonnell, None; G.J. McLellan, None; P. Mzyk, None; A. Nartey, None; L.R. Pasquale, None; G.C. Patel, None; P.P. Pattabiraman, None; D.M. Peters, None; V. Raghunathan, None; P.V. Rao, None; N. Rayana, None; U. Raychaudhuri, None; E. Reina-Torres, None; R. Ren, None; D. Rhee, None; U.R. Chowdhury, None; J.R. Samples, None; E.G. Samples, None; N. Sharif, None; J.S. Schuman, None; V.C. Sheffield, None; C.H. Stevenson, None; A. Soundararajan, None; P. Subramanian, None; C.K. Sugali, None; Y. Sun, None; C.B. Toris, None; K.Y. Torrejon, None; A. Vahabikashi, None; J.A. Vranka, None; T. Wang, None; C.E. Willoughby, None; C. Xin, None; H. Yun, None; H.F. Zhang, None; M.P. Fautsch, None; E.R. Tamm, None; A.F. Clark, None; C.R. Ethier, None; W.D. Stamer, None

Figures

Figure 1.
Figure 1.
Schematic diagram of outflow pathway and structures in the trabecular meshwork. (A) Schematic diagram depicting conventional and uveoscleral pathway in the anterior eye chamber. (B) A magnified view of trabecular meshwork (TM) depicting distal regions including collector channel entrances (CCEs), collector channels (CCs), episcleral vein (EV), and aqueous vein (AV). CB, ciliary body; SC, Schlemm's canal; IW, inner wall; JCT, juxtacanalicular. Reprinted with permission from Carreon T, van der Merwe E, Fellman RL, Johnstone M, Bhattacharya SK. Aqueous outflow - a continuum from trabecular meshwork to episcleral veins. Prog Retin Eye Res. 2017;57:108–133.
Figure 2.
Figure 2.
Histogram of measured facilities (C) in wild-type C57BL/6J enucleated mouse eyes. The lognormal distribution is clearly evident. The modal facility value is 3 to 6 nL/min/mmHg. Inset shows the same data, after log transformation. Reprinted with permission from Reina-Torres E, Bertrand JA, O'Callaghan J, Sherwood JM, Humphries P, Overby DR. Reduced humidity experienced by mice in vivo coincides with reduced outflow facility measured ex vivo. Exp Eye Res. 2019;186:107745. © 2019 Elsevier Ltd.
Figure 3.
Figure 3.
Linearity of pressure–flow rate curve in live mice. (A) C57BL/6J mouse pressure–flow rate curve (N = 6 eyes in situ in live animals; AC perfusion). Over the flow rate range of 100 to 500 nL/min, corresponding to a mean pressure of 15.58 ± 2.83 to 35.18 ± 4.26 mmHg (mean ± square deviation from the mean [SDM]), the curve approached linearity: r2 = 0.9891 ± 0.0076 (mean ± SDM); AIC (two-level linear nested design) = 128.2; AIC (three-level linear nested design) = 130. Computed facility = 19.5 ± 0.8 nL/min/mmHg (mean ± SEM). (B) C57BL/6J mouse pressure–flow rate curve (N = 6 eyes in situ in live animals; PC perfusion). Over the flow rate range of 100 to 500 nL/min, corresponding to a mean pressure of 13.36 ± 2.77 to 33.21 ± 5.57 mmHg (mean ± SDM), the curve approached linearity: r2 = 0.9882 ± 0.0032 (mean ± SDM); AIC (two-level linear nested design) = 156.2; AIC (three-level linear nested design) = 155.9. Computed facility = 21.0 ± 2.1 nL/min/mmHg (mean ± SEM). Reprinted with permission from Lopez NN, Patel GC, Raychaudhuri U, et al. Anterior chamber perfusion versus posterior chamber perfusion does not influence measurement of aqueous outflow facility in living mice by constant flow infusion. Exp Eye Res. 2017;164:95–108. © 2017 Elsevier Ltd.
Figure 4.
Figure 4.
Examples of appropriate histological examination of the outflow pathway. (A, B) Semithin sections (Richardson's stain) through the iridocorneal angle of representative control and Cav-1 knockout (KO) eyes. The chamber angle is open in control and Cav-1 KO eyes, and obvious abnormalities of the CB, TM, and SC are absent. (C, D) Ultrastructural changes in the JCT region of mice treated with or without dexamethasone (DEX) for 3 to 4 weeks. (C) In sham-treated control mice without DEX, optically open spaces (stars) were often observed between JCT cells with processes extending in many directions. (D) In DEX-treated mice, the JCT was often filled with fine fibrillar material (arrows), and the JCT cells appeared elongated. TL, trabecular lamellae. A and B are reprinted from Elliott MH, Ashpole NE, Gu X, et al. Caveolin-1 modulates intraocular pressure: implications for caveolae mechanoprotection in glaucoma. Sci Rep. 2016;6:37127. C and D are reprinted with permission from Overby DR, Bertrand J, Tektas OY, et al. Ultrastructural changes associated with dexamethasone-induced ocular hypertension in mice. Invest Ophthalmol Vis Sci. 2014;55:4922–4933. © 2014 Association for Research in Vision and Ophthalmology.
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References

    1. Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Collaborative Normal-Tension Glaucoma Study Group. Am J Ophthalmol. 1998; 126: 498–505. - PubMed
    1. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol. 2000; 130: 429–440. - PubMed
    1. Gordon MO, Beiser JA, Brandt JD, et al. .. The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002; 120: 714–720; discussion 829–830. - PubMed
    1. Higginbotham EJ, Gordon MO, Beiser JA, et al. .. The Ocular Hypertension Treatment Study: topical medication delays or prevents primary open-angle glaucoma in African American individuals. Arch Ophthalmol. 2004; 122: 813–820. - PubMed
    1. Leske MC, Heijl A, Hyman L, Bengtsson B.. Early Manifest Glaucoma Trial: design and baseline data. Ophthalmology. 1999; 106: 2144–2153. - PubMed

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