Pathophysiology Of Glaucoma Research Articles

Optic Nerve Head Blood Flow Response to Reduced Ocular Perfusion Pressure by Alteration of Either the Blood Pressure or Intraocular Pressure

Purpose: To test the hypothesis that blood flow autoregulation in the optic nerve head has less reserve to maintain normal blood flow in the face of blood pressure-induced ocular perfusion pressure decrease than a similar magnitude intraocular pressure-induced ocular perfusion pressure decrease.Materials and methods: Twelve normal non-human primates were anesthetized by continuous intravenous infusion of pentobarbital. Optic nerve blood flow was monitored by laser speckle flowgraphy. In the first group of animals (n = 6), the experimental eye intraocular pressure was maintained at 10 mmHg using a saline reservoir connected to the anterior chamber. The blood pressure was gradually reduced by a slow injection of pentobarbital. In the second group (n = 6), the intraocular pressure was slowly increased from 10 mmHg to 50 mmHg by raising the reservoir. In both experimental groups, optic nerve head blood flow was measured continuously. The blood pressure and intraocular pressure were simultaneously recorded in all experiments.Results: The optic nerve head blood flow showed significant difference between the two groups (p = 0.021, repeat measures analysis of variance). It declined significantly more in the blood pressure group compared to the intraocular pressure group when the ocular perfusion pressure was reduced to 35 mmHg (p < 0.045) and below. There was also a significant interaction between blood flow changes and the ocular perfusion pressure treatment (p = 0.004, adjusted Greenhouse & Geisser univariate test), indicating the gradually enlarged blood flow difference between the two groups was due to the ocular perfusion pressure decrease.Conclusions: The results show that optic nerve head blood flow is more susceptible to an ocular perfusion pressure decrease induced by lowering the blood pressure compared with that induced by increasing the intraocular pressure. This blood flow autoregulation capacity vulnerability to low blood pressure may provide experimental evidence related to the hemodynamic pathophysiology in glaucoma.

The pathophysiology and treatment of glaucoma: a review.

Glaucoma is a worldwide leading cause of irreversible vision loss. Because it may be asymptomatic until a relatively late stage, diagnosis is frequently delayed. A general understanding of the disease pathophysiology, diagnosis, and treatment may assist primary care physicians in referring high-risk patients for comprehensive ophthalmologic examination and in more actively participating in the care of patients affected by this condition. To describe current evidence regarding the pathophysiology and treatment of open-angle glaucoma and angle-closure glaucoma. A literature search was conducted using MEDLINE, the Cochrane Library, and manuscript references for studies published in English between January 2000 and September 2013 on the topics open-angle glaucoma and angle-closure glaucoma. From the 4334 abstracts screened, 210 articles were selected that contained information on pathophysiology and treatment with relevance to primary care physicians. The glaucomas are a group of progressive optic neuropathies characterized by degeneration of retinal ganglion cells and resulting changes in the optic nerve head. Loss of ganglion cells is related to the level of intraocular pressure, but other factors may also play a role. Reduction of intraocular pressure is the only proven method to treat the disease. Although treatment is usually initiated with ocular hypotensive drops, laser trabeculoplasty and surgery may also be used to slow disease progression. Primary care physicians can play an important role in the diagnosis of glaucoma by referring patients with positive family history or with suspicious optic nerve head findings for complete ophthalmologic examination. They can improve treatment outcomes by reinforcing the importance of medication adherence and persistence and by recognizing adverse reactions from glaucoma medications and surgeries.

Taurine: The comeback of a neutraceutical in the prevention of retinal degenerations

Taurine is the most abundant amino acid in the retina. In the 1970s, it was thought to be involved in retinal diseases with photoreceptor degeneration, because cats on a taurine-free diet presented photoreceptor loss. However, with the exception of its introduction into baby milk and parenteral nutrition, taurine has not yet been incorporated into any commercial treatment with the aim of slowing photoreceptor degeneration. Our recent discovery that taurine depletion is involved in the retinal toxicity of the antiepileptic drug vigabatrin has returned taurine to the limelight in the field of neuroprotection. However, although the retinal toxicity of vigabatrin principally involves a deleterious effect on photoreceptors, retinal ganglion cells (RGCs) are also affected. These findings led us to investigate the possible role of taurine depletion in retinal diseases with RGC degeneration, such as glaucoma and diabetic retinopathy. The major antioxidant properties of taurine may influence disease processes. In addition, the efficacy of taurine is dependent on its uptake into retinal cells, microvascular endothelial cells and the retinal pigment epithelium. Disturbances of retinal vascular perfusion in these retinal diseases may therefore affect the retinal uptake of taurine, resulting in local depletion. The low plasma taurine concentrations observed in diabetic patients may further enhance such local decreases in taurine concentration. We here review the evidence for a role of taurine in retinal ganglion cell survival and studies suggesting that this compound may be involved in the pathophysiology of glaucoma or diabetic retinopathy. Along with other antioxidant molecules, taurine should therefore be seriously reconsidered as a potential treatment for such retinal diseases.

Gene expression-based comparison of the human secretory neuroepithelia of the brain choroid plexus and the ocular ciliary body: potential implications for glaucoma

BackgroundThe neuroepithelia of the choroid plexus (CP) in the brain and the ciliary body (CB) of the eye have common embryological origins and share similar micro-structure and functions. The CP epithelium (CPE) and the non-pigmented epithelium (NPE) of the CB produce the cerebrospinal fluid (CSF) and the aqueous humor (AH) respectively. Production and outflow of the CSF determine the intracranial pressure (ICP); production and outflow of the AH determine the intraocular pressure (IOP). Together, the IOP and ICP determine the translaminar pressure on the optic disc which may be involved in the pathophysiology of primary open angle glaucoma (POAG). The aim of this study was to compare the molecular machinery of the secretory neuroepithelia of the CP and CB (CPE versus NPE) and to determine their potential role in POAG.MethodsWe compared the transcriptomes and functional annotations of healthy human CPE and NPE. Microarray and bioinformatic studies were performed using an Agilent platform and the Ingenuity Knowledge Database (IPA).ResultsBased on gene expression profiles, we found many similar functions for the CPE and NPE including molecular transport, neurological disease processes, and immunological functions. With commonly-used selection criteria (fold-change > 2.5, p-value < 0.05), 14% of the genes were expressed significantly differently between CPE and NPE. When we used stricter selection criteria (fold-change > 5, p-value < 0.001), still 4.5% of the genes were expressed differently, which yielded specific functions for the CPE (ciliary movement and angiogenesis/hematopoiesis) and for the NPE (neurodevelopmental properties). Apart from a few exceptions (e.g. SLC12A2, SLC4A4, SLC4A10, KCNA5, and SCN4B), all ion transport protein coding genes involved in CSF and AH production had similar expression profiles in CPE and NPE. Three POAG disease genes were expressed significantly higher in the CPE than the NPE, namely CDH1, CDKN2B and SIX1.ConclusionsThe transcriptomes of the CPE and NPE were less similar than we previously anticipated. High expression of CSF/AH production genes and candidate POAG disease genes in the CPE and NPE suggest that both might be involved in POAG.

Von Willebrand factor in iris vasculature of glaucoma patients.

BackgroundPrevious reports have indicated the role of endothelium disturbances, as expressed by von Willebrand factor (vWF) release, in pathophysiology of glaucoma. The objective of this study was to investigate the vWF expression in iris vasculature of patients with primary open-angle glaucoma (POAG).Material/MethodsImmunohistochemistry of vWF expression was performed on cryostat sections of samples collected at the time of peripheral iridectomy and controls collected from dead donors.ResultsTwenty-seven Caucasians age 66.6±3.7 with 5.8±3.7-year history of treated PAOG and 10 controls age 62.2±1.92 with no history of glaucoma. The percentage of patients who presented normal and up-regulation of vWF phenotype expression differed statistically between examined and control groups: 48% versus 100% (p=0.035, chi-square test with Yates’ correction). Sex, age, glaucoma duration, and visual field quantitative indices had no impact on vWF expression. A significant correlation between mean pre-surgery intraocular pressure and vWF expression was found (Spearman r=0.42, p=0.03).ConclusionsConsidering the results, it may be suggested that vWF is actively involved in the pathophysiology of glaucoma.

Astrocyte Reactivity: A Biomarker for Retinal Ganglion Cell Health in Retinal Neurodegeneration.

Retinal ganglion cell (RGC) loss in glaucoma is sectorial in nature and preceded by deficits in axonal transport. Neuroinflammation plays an important role in the pathophysiology of glaucoma in the retina, optic nerve and visual centers of the brain, where it similarly appears to be regulated spatially. In a murine model, we examined the spatial characteristics of astrocyte reactivity (migration/proliferation, hypertrophy and GFAP expression) in healthy retina, retina with two glaucoma-related risk factors (aging and genetic predisposition) and glaucomatous retina and established relationships between these reactivity indices and the spatial organization of astrocytes as well as RGC health. Astrocyte reactivity was quantified by morphological techniques and RGC health was determined by uptake and transport of the neural tracer cholera toxin beta subunit (CTB). We found that: (1) astrocyte reactivity occurs in microdomains throughout glaucomatous retina as well as retina with risk factors for glaucoma, (2) these astrocyte microdomains are primarily differentiated by the degree of retinal area covered by the astrocytes within them and (3) percent retinal area covered by astrocytes is highly predictive of RGC health. Our findings suggest that microdomains of astrocyte reactivity are biomarkers for functional decline of RGCs. Based on current and emerging imaging technologies, diagnostic assessment of astrocytes in the nerve fiber layer could succeed in translating axonal transport deficits to a feasible clinical application.

Genomic and proteomic pathophysiology of pseudoexfoliation glaucoma.

PEX stems from a pathologic elastotic process involving the cross-linking gene lysyl oxidase-like-1 (LOXL1), and is associated with abnormal formation of elastic extracellular matrix. We previously described a protein sink model to explain PEX material deposition on the lens capsule and other intraocular surfaces. Recent research findings not only provide evidence to support this hypothesis, but also further our understanding of the fundamental disease process. A key aspect of the pathogenic process is the compromise of blood-aqueous barrier integrity in PEXG. Decreased level of LOXL1 is associated with decreased elastin incorporation into elastic tissues, including the elastic lamina of blood vessels. This results in unincorporated elastin that is released as soluble elastin, and leakage of serum proteins, inflammatory cytokines, and extracellular matrix components into aqueous humor. This ultimately leads to aggregation and precipitation of large protein complexes, or PEX material, throughout intraocular surfaces as described in the protein sink model. The pathologic PEX process also affects the biomechanical properties of elastic tissues, such as the trabecular meshwork, lens zonules, and lamina cribrosa. This may be part of the primary pathologic process with intrinsically altered extracellular matrix proteins. This fundamental change in the structural composition of these tissues may alter their rigidity, elasticity, and other biomechanical properties. This likely contributes to increased trabecular meshwork outflow resistance and high intraocular pressure, and mechanical injury to retinal ganglion cell axons at the lamina cribrosa, which are conducive to glaucoma. These pathophysiologic processes combined may underlie some of the clinical hallmarks observed in PEXG.

Ocular Manifestations of 22q11.2 Microduplication

To report a new ocular manifestation of the dup22q11 syndrome and explore involved genes that may offer insight to mechanisms of pathogenesis. Case series. Two male patients with this syndrome diagnosed with dup22q11.2. Medical records were reviewed. Duplication was detected in the oligo-single nucleotide polymorphism chromosomal microarray and duplicated genes within the segment where determined by literature and database review. Potential associations between the ophthalmologic manifestations and their physiopathology were investigated. Microarray results and identification of candidate genes within the duplicated segment. Our patients demonstrate previously unreported findings of dup22q11.2, including Marcus Gunn jaw winking, Duane's retraction syndrome, and other abnormal eye movements consistent with a congenital cranial dysinnervation disorder (CCDD), retinal vascular tortuosity, and primary infantile glaucoma. The duplicated segment in case 1 includes SNAP29, which could be linked with the development of retinal vascular tortuosity, and MAPK1, which seems to play a role in axonal development through the semaphorin pathway, which may serve as a candidate gene for CCDD. In case 2, the CLDN5 gene is within the duplicated segment. CLDN5 could be involved in the pathophysiology of glaucoma. Our cases expand the ocular phenotype for duplication of 22q11 and serve to identify potential candidate genes for the development of CCDD, retinal vascular tortuosity, and glaucoma.

Retinal oxygen: the good, the bad and the unknown?

AbstractIschemia is suspected in the pathophysiology of several eye diseases including glaucoma. The most direct way to study ischemia is through blood flow and circulatory studies and these have shown abnormalities in glaucoma and other eye diseases. However, blood flow changes per se do not necessarily indicate an unhealthy situation; blood flow indeed varies substantially in healthy tissues. The main metabolic consequence of ischemia is hypoxia and any harmful consequence of ischemia must include hypoxia at some point in time. Therefore, oxygen measurements are a direct way to study pathogenesis in ischemic diseases. Tissue damage would involve hypoxia and lack of hypoxia is not fully consistent with ischemic pathophysiology. The fact that hypoxia has to date not been found in glaucoma patients, suggests that ischemia may not be involved in the pathophysiology of glaucoma. The abnormalities in blood flow and oxygenation seen in glaucoma may be secondary to tissue atrophy, rather than the cause of the disease. Further studies, especially in patients with progressive glaucoma and high intraocular pressure will clarify the issue.

Glaucoma and optic nerve repair

Glaucoma is a leading cause of irreversible blindness worldwide and causes progressive visual impairment attributable to the dysfunction and death of retinal ganglion cells (RGCs). Progression of visual field damage is slow and typically painless. Thus, glaucoma is often diagnosed after a substantial percentage of RGCs has been damaged. To date, clinical interventions are mainly restricted to the reduction of intraocular pressure (IOP), one of the major risk factors for this disease. However, the lowering of IOP is often insufficient to halt or reverse the progress of visual loss, underlining the need for the development of alternative treatment strategies. Several lines of evidence suggest that axonal damage of RGCs occurs primary at the optic nerve head, where axons appear to be most vulnerable. Axonal injury leads to the functional loss of RGCs and subsequently induces the death of the neurons. However, the detailed molecular mechanism(s) underlying IOP-induced optic nerve injury remain poorly understood. Moreover, whether glaucoma pathophysiology is primarily axonal, glial, or vascular remains unclear. Therefore, protective strategies to prevent further axonal and subsequent soma degeneration are of great importance to limit the progression of sight loss. In addition, strategies that stimulate injured RGCs to regenerate and reconnect axons with their central targets are necessary for functional restoration. The present review provides an overview of the context of glaucoma pathogenesis and surveys recent findings regarding potential strategies for axonal regeneration of RGCs and optic nerve repair, focusing on the role of cytokines and their downstream signaling pathways.

Direct trabecular meshwork imaging in porcine eyes through multiphoton gonioscopy

.The development of technologies to characterize the ocular aqueous outflow system (AOS) is important for the understanding of the pathophysiology of glaucoma. Multiphoton microscopy (MPM) offers the advantage of high-resolution, label-free imaging with intrinsic image contrast because the emitted signals result from the specific biomolecular content of the tissue. Previous attempts to use MPM to image the murine irido-corneal region directly through the sclera have suffered from degradation in image resolution due to scattering of the focused laser light. As a result, transscleral MPM has limited ability to observe fine structures in the AOS. In this work, the porcine irido-corneal angle was successfully imaged through the transparent cornea using a gonioscopic lens to circumvent the highly scattering scleral tissue. The resulting high-resolution images allowed the detailed structures in the trabecular meshwork (TM) to be observed. Multimodal imaging by two-photon autofluorescence and second harmonic generation allowed visualization of different features in the TM without labels and without disruption of the TM or surrounding tissues. MPM gonioscopy is a promising noninvasive imaging tool for high-resolution studies of the AOS, and research continues to explore the potential for future clinical applications in humans.

Ocular Hemodynamics and Glaucoma: The Role of Mathematical Modeling

To discuss the role of mathematical modeling in studying ocular hemodynamics, with a focus on glaucoma. We reviewed recent literature on glaucoma, ocular blood flow, autoregulation, the optic nerve head, and the use of mathematical modeling in ocular circulation. Many studies suggest that alterations in ocular hemodynamics play a significant role in the development, progression, and incidence of glaucoma. Although there is currently a limited number of studies involving mathematical modeling of ocular blood flow, regulation, and diseases (such as glaucoma), preliminary modeling work shows the potential of mathematical models to elucidate the mechanisms that contribute most significantly to glaucoma progression. Mathematical modeling is a useful tool when used synergistically with clinical and laboratory data in the study of ocular blood flow and glaucoma. The development of models to investigate the relationship between ocular hemodynamic alterations and glaucoma progression will provide a unique and useful method for studying the pathophysiology of glaucoma.

Analysis of Pulsatile Retinal Movements by Spectral-Domain Low-Coherence Interferometry: Influence of Age and Glaucoma on the Pulse Wave

Recent studies have shown that ocular hemodynamics and eye tissue biomechanical properties play an important role in the pathophysiology of glaucoma. Nevertheless, better, non-invasive methods to assess these characteristics in vivo are essential for a thorough understanding of degenerative mechanisms. Here, we propose to measure ocular tissue movements induced by cardiac pulsations and study the ocular pulse waveform as an indicator of tissue compliance. Using a novel, low-cost and non-invasive device based on spectral-domain low coherence interferometry (SD-LCI), we demonstrate the potential of this technique to differentiate ocular hemodynamic and biomechanical properties. We measured the axial movement of the retina driven by the pulsatile ocular blood flow in 11 young healthy individuals, 12 older healthy individuals and 15 older treated glaucoma patients using our custom-made SD-OCT apparatus. The cardiac pulse was simultaneously measured through the use of an oximeter to allow comparison. Spectral components up to the second harmonic were obtained and analyzed. For the different cohorts, we computed a few parameters that characterize the three groups of individuals by analyzing the movement of the retinal tissue at two locations, using this simple, low-cost interferometric device. Our pilot study indicates that spectral analysis of the fundus pulsation has potential for the study of ocular biomechanical and vascular properties, as well as for the study of ocular disease.

Shotgun proteomics reveals specific modulated protein patterns in tears of patients with primary open angle glaucoma naïve to therapy

Primary open angle glaucoma (POAG) is one of the main causes of irreversible blindness worldwide. The pathogenesis of POAG is still unclear. Alteration and sclerosis of trabecular meshwork with changes in aqueous humor molecular composition seem to play the key role. Increased intraocular pressure is widely known to be the main risk factor for the onset and progression of the disease. Unfortunately, the early diagnosis of POAG still remains the main challenge. In order to provide insight into the patho-physiology of glaucoma, here we report a shotgun proteomics approach to tears of patients with POAG naïve to therapy. Our proteomics results showed 27 differential tear proteins in POAG vs. CTRL comparison (25 up regulated proteins in the POAG group and two unique proteins in the CTRL group), 16 of which were associated with inflammatory response, free radical scavenging, cell-to-cell signaling and interaction. Overall the protein modulation shown in POAG tears proves the involvement of biochemical networks linked to inflammation. Among all regulated proteins, a sub-group of 12 up-regulated proteins in naïve POAG patients were found to be down-regulated in medically controlled POAG patients treated with prostanoid analogues (PGA), as reported in our previous work (i.e., lipocalin-1, lysozyme C, lactotransferrin, proline-rich-protein 4, prolactin-inducible protein, zinc-alpha-2-glycoprotein, polymeric immunoglobulin receptor, cystatin S, Ig kappa chain C region, Ig alpha-2 chain C region, immunoglobulin J chain, Ig alpha-1 chain C region). In summary, our findings indicate that the POAG tears protein expression is a mixture of increased inflammatory proteins that could be potential biomarkers of the disease, and their regulation may be involved in the mechanism by which PGA are able to decrease the intraocular pressure in glaucoma patients.

A New Safety Concern for Glaucoma Treatment Demonstrated by Mass Spectrometry Imaging of Benzalkonium Chloride Distribution in the Eye, an Experimental Study in Rabbits

We investigated in a rabbit model, the eye distribution of topically instilled benzalkonium_(BAK) chloride a commonly used preservative in eye drops using mass spectrometry imaging. Three groups of three New Zealand rabbits each were used: a control one without instillation, one receiving 0.01%BAK twice a day for 5 months and one with 0.2%BAK one drop a day for 1 month. After sacrifice, eyes were embedded and frozen in tragacanth gum. Serial cryosections were alternately deposited on glass slides for histological (hematoxylin-eosin staining) and immunohistological controls (CD45, RLA-DR and vimentin for inflammatory cell infiltration as well as vimentin for Müller glial cell activation) and ITO or stainless steel plates for MSI experiments using Matrix-assisted laser desorption ionization time-of-flight. The MSI results were confirmed by a round-robin study on several adjacent sections conducted in two different laboratories using different sample preparation methods, mass spectrometers and data analysis softwares. BAK was shown to penetrate healthy eyes even after a short duration and was not only detected on the ocular surface structures, but also in deeper tissues, especially in sensitive areas involved in glaucoma pathophysiology, such as the trabecular meshwork and the optic nerve areas, as confirmed by images with histological stainings. CD45-, RLA-DR- and vimentin-positive cells increased in treated eyes. Vimentin was found only in the inner layer of retina in normal eyes and increased in all retinal layers in treated eyes, confirming an activation response to a cell stress. This ocular toxicological study confirms the presence of BAK preservative in ocular surface structures as well as in deeper structures involved in glaucoma disease. The inflammatory cell infiltration and Müller glial cell activation confirmed the deleterious effect of BAK. Although these results were obtained in animals, they highlight the importance of the safety-first principle for the treatment of glaucoma patients.

Role of rs1533428 and rs12994401 in patients with Primary Open Angle Glaucoma in an European population

Purpose: Genetic factors have been shown to play a remarkable role in the pathophysiology of glaucoma. Recently, two polymorphisms (rs1533428 and rs12994401) on chromosome 2p were found to be strongly associated with POAG in an Afro-Caribbean population in Barbados, West Indies. As data with regard to the role of these polymorphisms in a Caucasian population are lacking, the present study was set to investigate a hypothetical association between these polymorphisms and POAG in a Caucasian population.Methods: In total 723 participants were included in this study comprising 366 patients with POAG and 357 control subjects from the southern part of Austria. Genotyping of rs1533428 and rs12994401 was performed using polymerase chain reaction.Results: Allelic frequencies and genotype distributions of rs1533428 and rs12994401 did not show statistical significance between patients with POAG and control subjects (p < 0.05). Presence of the rs1533428 T-allele was associated with an odds ratio of 0.95 (95% CI: 0.76–1.19; p = 0.69) for POAG, while the rs12994401 T-allele was associated with an odds ratio of 0.94 (95% CI: 0.73–1.21; p = 0.65) for POAG.Conclusion: Our data suggest that rs1533428 and rs12994401 themselves are unlikely major risk factors for POAG in a Central European population.

Quantitative OCT angiography of optic nerve head blood flow

Optic nerve head (ONH) blood flow may be associated with glaucoma development. A reliable method to quantify ONH blood flow could provide insight into the vascular component of glaucoma pathophysiology. Using ultrahigh-speed optical coherence tomography (OCT), we developed a new 3D angiography algorithm called split-spectrum amplitude-decorrelation angiography (SSADA) for imaging ONH microcirculation. In this study, a method to quantify SSADA results was developed and used to detect ONH perfusion changes in early glaucoma. En face maximum projection was used to obtain 2D disc angiograms, from which the average decorrelation values (flow index) and the percentage area occupied by vessels (vessel density) were computed from the optic disc and a selected region within it. Preperimetric glaucoma patients had significant reductions of ONH perfusion compared to normals. This pilot study indicates OCT angiography can detect the abnormalities of ONH perfusion and has the potential to reveal the ONH blood flow mechanism related to glaucoma.

Characterization of a spontaneously immortalized bovine trabecular meshwork cell line

Trabecular meshwork (TM) cells have widely been used as an in vitro model for glaucoma research. However, primary TM cells suffer the disadvantages of limited cell numbers and slow rates of proliferation. We discovered a spontaneously transformed bovine TM (BTM) cell line, BTM-28T. This cell line proliferated rapidly in low-glucose culture medium but also demonstrated contact inhibition in high-glucose culture medium. BTM-28T cells expressed key TM cell markers including α-smooth muscle actin (α-SMA), laminin and collagen IV (col IV). Also, 100 nM dexamethasone (DEX) enhanced the formation of cross-linked actin networks (CLANs) in confluent BTM-28T cell cultures. Transforming growth factor beta 2 (TGFβ2) induced the expression of fibronectin (FN), plasminogen activator inhibitor-1 (PAI-1), and connective tissue growth factor (CTGF) in our cell cultures. This cell line will be helpful to better understand the aqueous humor outflow pathway as related to the pathophysiology of glaucoma.

Elevated Levels of RhoA in the Optic Nerve Head of Human Eyes With Glaucoma

To determine changes in the expression profile of RhoA and Rho kinase (ROCK-1 and ROCK-2) in the aqueous humor outflow pathway and optic nerve head (ONH) of human eyes with or without glaucoma to explore their potential involvement in glaucoma pathophysiology. Age-matched paraffin-embedded postmortem eyes from patients with or without glaucoma were stained immunohistochemically using polyclonal antibodies raised against RhoA, ROCK-1, and ROCK-2. The intensity of the immunostaining in the aqueous humor outflow pathway and the ONH was graded by 4 individuals who were masked concerning whether the eyes were from normal individuals or those with glaucoma. Both normal eyes and those with glaucoma showed a positive staining for RhoA, ROCK-1, and ROCK-2 in the trabecular meshwork, ciliary muscle, and ONH. There was a significant increase in the RhoA protein levels in the glaucomatous ONH compared with the age-matched controls. Elevated levels of RhoA in the ONH of glaucomatous eyes suggest possible involvement of RhoA in the pathophysiology of glaucoma.

Ocular perfusion pressure and ocular blood flow in glaucoma

Glaucoma is a progressive optic neuropathy of unknown origin. It has been hypothesized that a vascular component is involved in glaucoma pathophysiology. This hypothesis has gained support from studies showing that reduced ocular perfusion pressure is a risk factor for the disease. The exact nature of the involvement is, however, still a matter of debate. Based on recent evidence we propose a model including primary and secondary insults in glaucoma. The primary insult appears to happen at the optic nerve head. Increased intraocular pressure and ischemia at the post-laminar optic nerve head affects retinal ganglion cell axons. Modulating factors are the biomechanical properties of the tissues and cerebrospinal fluid pressure. After this primary insult retinal ganglion cells function at a reduced energy level and are sensitive to secondary insults. These secondary insults may happen if ocular perfusion pressure falls below the lower limit of autoregulation or if neurovascular coupling fails. Evidence for both faulty autoregulation and reduced hyperemic response to neuronal stimulation has been provided in glaucoma patients. The mechanisms appear to involve vascular endothelial dysfunction and impaired astrocyte-vessel signaling. A more detailed understanding of these pathways is required to direct neuroprotective strategies via the neurovascular pathway.