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Abstract
Outflow resistance in the aqueous drainage tract distal to trabecular meshwork is potentially an important determinant of intraocular pressure and success of trabecular bypass glaucoma surgeries. It is unclear how distal resistance is modulated. We sought to establish: (a) multimodal 2-photon deep tissue imaging and 3-dimensional analysis of the distal aqueous drainage tract (DT) in transgenic mice in vivo and ex vivo; (b) criteria for distinguishing the DT from blood and lymphatic vessels; and (c) presence of a DT wall organization capable of contractility. DT lumen appeared as scleral collagen second harmonic generation signal voids that could be traced back to Schlemm’s canal. DT endothelium was Prox1-positive, CD31-positive and LYVE-1-negative, bearing a different molecular signature from blood and true lymphatic vessels. DT walls showed prominent filamentous actin (F-actin) labeling reflecting cells in a contracted state. F-actin co-localized with mesenchymal smooth muscle epitopes of alpha-smooth muscle actin, caldesmon and calponin, which localized adjacent and external to the endothelium. Our findings support a DT wall organization resembling that of blood vessels. This reflects a capacity to contract and support dynamic alteration of DT caliber and resistance analogous to the role of blood vessel tone in regulating blood flow.
Highlights
Glaucoma is the leading cause of irreversible blindness worldwide and intraocular pressure (IOP) is a major risk factor for the disease
Imaging of hybrid cell membrane-localized td-Tomato and cytosolic green fluorescent protein (GFP) co-expressing transgenic reporter mice revealed an interconnected network of intrascleral channels
We have assembled tools for tissue-based and in vivo studies of the mouse to address goals to: (1) identify and verify the drainage tract (DT) in deep tissue imaging; (2) digitally map the 3-dimensionally complex DT and its relationships; (3) better characterize the unique endothelial molecular signature of the DT relative to lymphatic and blood vessels; (4) explore the possibility that the DT has capacity to contract and carries a smooth muscle identity mimicking that of blood vessels; and (5) compare the DT profile of contractile markers with that of proximal drainage tissues of the trabecular meshwork (TM) and ciliary muscle (CM)
Summary
Glaucoma is the leading cause of irreversible blindness worldwide and intraocular pressure (IOP) is a major risk factor for the disease. The clinical importance of the DT has been brought into fresh focus by newer glaucoma surgeries that bypass TM resistance by incising the TM or inserting drainage stents through it Following these procedures, IOP may be lowered but generally not to the anticipated level of episcleral venous pressure (EVP). We conducted tissue-based studies to characterize the fine structure and aspects of the molecular identity of the DT and explore whether it has contractile features We studied this in mice as its aqueous drainage tract is similar to that of primates in structure and function[13,14,15,16,17,18,19]. While blood vessel endothelium and DT endothelium share in common expression of typical endothelial markers such as vascular endothelial growth factor receptor 2 (VEGFR2), platelet endothelial cell adhesion molecule 1 (PECAM-1 or CD31) and vascular endothelial cadherin (VE-cadherin), blood vessels do not express lymphatic endothelial markers such as Prox[127–30]
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