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Aqueous Angiography in Living Nonhuman Primates Shows Segmental, Pulsatile, and Dynamic Angiographic Aqueous Humor Outflow.

ABSTRACT: To evaluate the feasibility of safely performing aqueous angiography in intact eyes of living nonhuman primates (NHPs) for evaluating aqueous humor outflow and segmental patterns.Cross-sectional, observational study.Six nonhuman primates.Aqueous angiography was performed in 6 nonhuman primates. After anesthesia, an anterior chamber (AC) maintainer was placed through a temporal 1-mm side-port wound. Indocyanine green (ICG; 0.4%) or 2.5% fluorescein was introduced (individually or in sequence) into the eye with a gravity-driven constant-pressure system. Aqueous angiography images were obtained with a Spectralis HRA+OCT (Heidelberg Engineering GmbH, Heidelberg, Germany) suspended over the NHP eye using a custom-designed surgical boom arm. Concurrent anterior segment optical coherence tomography (OCT) was performed on distally angiographically positive and negative regions.Angiographic patterns described by location, time-course, choice of tracer, and anterior-segment OCT.Aqueous angiography in the living NHP eye demonstrated mostly stable angiographic patterns. With multimodal imaging, angiographically positive signal co-localized with episcleral veins as identified by infrared imaging and intrascleral lumens, as demonstrated by anterior segment OCT. Sequential aqueous angiography in individual eyes with ICG followed by fluorescein showed similar angiographic patterns. A pulsatile nature of aqueous angiographic outflow was sometimes observed. Aqueous angiographic patterns could also dynamically change. In some instances, positive angiographic flow suddenly arose in regions previously without an angiographic signal. Alternatively, an angiographic signal could suddenly disappear from regions in which an angiographic signal was initially documented.Aqueous angiography in living NHPs demonstrated segmental and pulsatile patterns with a newly described ability to dynamically shift. These characteristics further the understanding of live aqueous humor outflow biology and may be useful in improving glaucoma surgeries aimed at trabecular meshwork bypass.

SUBMITTER: Huang AS

PROVIDER: S-EPMC5484000 | biostudies-other | 2017 Jun

REPOSITORIES: biostudies-other

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Aqueous Angiography in Living Nonhuman Primates Shows Segmental, Pulsatile, and Dynamic Angiographic Aqueous Humor Outflow.

Huang Alex S AS Li Meng M Yang Diya D Wang Huaizhou H Wang Ningli N Weinreb Robert N RN

Ophthalmology 20170223 6

<h4>Purpose</h4>To evaluate the feasibility of safely performing aqueous angiography in intact eyes of living nonhuman primates (NHPs) for evaluating aqueous humor outflow and segmental patterns.<h4>Design</h4>Cross-sectional, observational study.<h4>Subjects</h4>Six nonhuman primates.<h4>Methods</h4>Aqueous angiography was performed in 6 nonhuman primates. After anesthesia, an anterior chamber (AC) maintainer was placed through a temporal 1-mm side-port wound. Indocyanine green (ICG; 0.4%) or 2 ...[more]

PMID: 28237425

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Project description:Herein partially summarizes one scientist-clinician's wanderings through the jungles of primate aqueous humor outflow over the past ~45 years. Totally removing the iris has no effect on outflow facility or its response to pilocarpine, whereas disinserting the ciliary muscle (CM) from the scleral spur/trabecular meshwork (TM) completely abolishes pilocarpine's effect. Epinephrine increases facility in CM disinserted eyes. Cytochalasins and latrunculins increase outflow facility, subthreshold doses of cytochalasins and epinephrine given together increase facility, and phalloidin, which has no effect on facility, partially blocks the effect of both cytochalasins and epinephrine. H-7, ML7, Y27632 and nitric oxide - donating compounds all increase facility, consistent with a mechanosensitive TM/SC. Adenosine A1 agonists increase and angiotensin II decrease facility. OCT and optical imaging techniques now permit visualization and digital recording of the distal outflow pathways in real time. Prostaglandin (PG) F2α analogues increase the synthesis and release of matrix metalloproteinases by the CM cells, causing remodeling and thinning of the interbundle extracellular matrix (ECM), thereby increasing uveoscleral outflow and reducing IOP. Combination molecules (one molecule, two or more effects) and fixed combination products (two molecules in one bottle) simplify drug regimens for patients. Gene and stem cell therapies to enhance aqueous outflow have been successful in laboratory models and may fill an unmet need in terms of patient compliance, taking the patient out of the delivery system. Functional transfer of genes inhibiting the rho cascade or decoupling actin from myosin increase facility, while genes preferentially expressed in the glaucomatous TM decrease facility. In live NHP, reporter genes are expressed for 2+ years in the TM after a single intracameral injection, with no adverse reaction. However, except for one recent report, injection of facility-effective genes in monkey organ cultured anterior segments (MOCAS) have no effect in live NHP. While intracameral injection of an FIV. BOVPGFS-myc.GFP PGF synthase vector construct reproducibly induces an ~2 mmHg reduction in IOP, the effect is much less than that of topical PGF2⍺ analogue eyedrops, and dissipates after 5 months. The turnoff mechanism has yet to be defeated, although proteasome inhibition enhances reporter gene expression in MOCAS. Intracanalicular injection might minimize off-target effects that activate turn-off mechanisms. An AD-P21 vector injected sub-tenon is effective in 'right-timing' wound healing after trabeculectomy in live laser-induced glaucomatous monkeys. In human (H)OCAS, depletion of TM cells by saponification eliminates the aqueous flow response to pressure elevation, which can be restored by either cultured TM cells or by IPSC-derived TM cells. There were many other steps along the way, but much was accomplished, biologically and therapeutically over the past half century of research and development focused on one very small but complex ocular apparatus. I am deeply grateful for this award, named for a giant in our field that none of us can live up to.

Dataset Information

Aqueous Angiography in Living Nonhuman Primates Shows Segmental, Pulsatile, and Dynamic Angiographic Aqueous Humor Outflow.

Publications

Aqueous Angiography in Living Nonhuman Primates Shows Segmental, Pulsatile, and Dynamic Angiographic Aqueous Humor Outflow.

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