Retinovascular physiology and pathophysiology: New experimental approach/new insights

Puro, Donald G.

doi:10.1016/j.preteyeres.2012.01.001

Cited by 45 publications

(44 citation statements)

References 71 publications

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“…Nonetheless, because the fundamental mechanisms for hypoxia-driven neovascularization almost certainly evolved to meet the needs of nonretinal tissues, we posit that this may be the case. With retinal neovascularization only recently impacting health owing to increased life expectancies of premature infants and patients with diabetes or sickle cell disease, there has been little time for evolutionary pressure to optimize neovascular mechanisms to meet the unique anatomic and physiological challenges of the retina (30). In nonretinal tissues, neovascularization is well adapted to enhance functional recovery; for example, in stark contrast to pathological retinal angiogenesis, vasoproliferation in hypoxic muscle is a highly effective adaptive response, even though the neovessels grow aberrantly and fail to replicate the pattern of the original vascular network (31).…”

Section: Discussionmentioning

confidence: 99%

“…Another experimental preparation consisted of preretinal neovascular tissue excised from adult patients with diabetes undergoing surgery for sightthreatening complications of proliferative retinopathy. A third preparation consisted of microvessels (i.e., <20-μm diameter) freshly isolated from the retinas of normal and ROP rats aged P30-P60 (30). The vessels isolated from ROP retinas often contained ∼15-to 25-μm-diameter multicellular complexes with a positivity for the endothelial cell marker isolectin GS-IB 4 (Fig.…”

Section: Methodsmentioning

confidence: 99%

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Bioelectric impact of pathological angiogenesis on vascular function

Puro

Kohmoto

Fujita

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Pathological angiogenesis, as seen in many inflammatory, immune, malignant, and ischemic disorders, remains an immense health burden despite new molecular therapies. It is likely that further therapeutic progress requires a better understanding of neovascular pathophysiology. Surprisingly, even though transmembrane voltage is well known to regulate vascular function, no previous bioelectric analysis of pathological angiogenesis has been reported. Using the perforated-patch technique to measure vascular voltages in human retinal neovascular specimens and rodent models of retinal neovascularization, we discovered that pathological neovessels generate extraordinarily high voltage. Electrophysiological experiments demonstrated that voltage from aberrantly located preretinal neovascular complexes is transmitted into the intraretinal vascular network. With extensive neovascularization, this voltage input is substantial and boosts the membrane potential of intraretinal blood vessels to a suprahyperpolarized level. Coincident with this suprahyperpolarization, the vasomotor response to hypoxia is fundamentally altered. Instead of the compensatory dilation observed in the normal retina, arterioles constrict in response to an oxygen deficiency. This anomalous vasoconstriction, which would potentiate hypoxia, raises the possibility that the bioelectric impact of neovascularization on vascular function is a previously unappreciated pathophysiological mechanism to sustain hypoxia-driven angiogenesis.neovascularization | proliferative retinopathy | retinopathy of prematurity | proliferative diabetic retinopathy | retina T he abnormal growth of blood vessels is a key pathophysiological feature of numerous disorders, including tumorigenesis, arthritis, endometriosis, and retinopathies. Despite substantial progress from studies of patients and animal models, abnormal neovascularization remains a common threat to health and wellbeing. To help address this challenge, we devised a unique experimental approach to better understand neovascular pathophysiology. Because almost nothing is known about the electrogenic profile of neovascular complexes and how these complexes functionally interact with their parent vessels, we focused on the bioelectric features of neovascularization. These gaps in knowledge are surprising, considering that it is well established that the transmembrane voltage of vascular cells (1), as well as electrotonic cell-cell interactions within a vascular network (2-4), play vital roles in regulating blood flow.In this electrophysiological analysis of pathological angiogenesis, we focused on abnormal vasoproliferation in rodent and human retinas. For multiple reasons, the retina is an ideal tissue for this undertaking. First is its clinical importance. Retinal vasoproliferation is the major cause of blindness in prematurely born infants (retinopathy of prematurity) and persons with diabetes (proliferative diabetic retinopathy) and sickle cell disease (sickle cell retinopathy). The hallmark of these disorders is abno...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Bioelectric impact of pathological angiogenesis on vascular function

Puro

Kohmoto

Fujita

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…1A). Analysis of glaucomatous retinas demonstrated that early vascular changes, characterized by the loss of capillaries (4-to 6-lm diameter 33,34 ), started 3 to 7 days after induction of OHT, a time when IOP increase was small (~3 mm Hg above basal, Table 1) (Figs. 1B, 1C).…”

Section: Loss Of the Retinal Microvasculature Begins Early And Occursmentioning

confidence: 99%

Acetylcholinesterase Inhibition Promotes Retinal Vasoprotection and Increases Ocular Blood Flow in Experimental Glaucoma

Almasieh

Macintyre

Pouliot

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. A clear correlation between vascular deficits and retinal ganglion cell (RGC) loss in glaucoma has not yet been established. The question arose as to whether there is loss of inner retinal vessels following intraocular pressure (IOP) increase and, if so, whether it occurs prior to, concomitantly with, or after RGC death. We also sought to establish whether galantamine, an acetylcholinesterase inhibitor that promotes RGC survival, can protect the retinal microvasculature and enhance blood flow in experimental glaucoma. METHODS. Ocular hypertension was induced in BrownNorway rats by injection of hypertonic saline into an episcleral vein. Retinas were processed for simultaneous visualization of the retinal microvasculature and RGCs in glaucomatous and control eyes. Retinal blood flow was examined by quantitative autoradiography using N-isopropyl-p-[14 C]-iodoamphetamine. Vascular reactivity was further assessed using an in vitro retinal microvasculature preparation.RESULTS. Substantial loss of retinal capillaries was observed after induction of ocular hypertension. The onset of both microvasculature and RGC loss occurred early and proceeded at a similar rate for at least 5 weeks after the initial damage. Systemic administration of galantamine preserved microvasculature density and improved retinal blood flow in glaucomatous retinas. The vasoactive effects of galantamine on retinal microvessels occurred through activation of muscarinic acetylcholine receptors both in vitro and in vivo.CONCLUSIONS. The onset and progression of microvessel and RGC loss are concomitant in experimental glaucoma, suggesting a tight codependence between these cellular compartments. Early interventions aimed to protect the retinal microvasculature and improve blood supply are likely to be beneficial for the treatment of glaucoma.

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“…NO generates hyperpolarizing currents that would be expected to relax pericytes and dilate the capillaries [43]. Vascular diameter responses can propagate between adjacent pericytes [15,44], but it is not known whether arterioles receive a signal to dilate from pericytes, or from vasoactive messengers, which reach arterioles later than they reach capillaries [17].…”

Section: Neuronal Control Of Blood Flow: a Role For Cholinergic Regulmentioning

confidence: 99%

Leveraging Optogenetic-Based Neurovascular Circuit Characterization for Repair

2016

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Optogenetic techniques are a powerful tool for determining the role of individual functional components within complex neural circuits. By genetically targeting specific cell types, neural mechanisms can be actively manipulated to gain a better understanding of their origin and function, both in health and disease. The potential of optogenetics is not limited to answering biological questions, as it is also a promising therapeutic approach for neurological diseases. An important prerequisite for this approach is to have an identified target with a uniquely defined role within a given neural circuit. Here, we examine the retinal neurovascular unit, a circuit that incorporates neurons and vascular cells to control blood flow in the retina. We highlight the role of a specific cell type, the cholinergic amacrine cell, in modulating vascular cells, and demonstrate how this can be targeted and controlled with optogenetics. A better understanding of these mechanisms will not only extend our understanding of neurovascular interactions in the brain, but ultimately may also provide new targets to treat vision loss in a variety of retinal diseases.

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Retinovascular physiology and pathophysiology: New experimental approach/new insights

Cited by 45 publications

References 71 publications

Bioelectric impact of pathological angiogenesis on vascular function

Bioelectric impact of pathological angiogenesis on vascular function

Acetylcholinesterase Inhibition Promotes Retinal Vasoprotection and Increases Ocular Blood Flow in Experimental Glaucoma

Leveraging Optogenetic-Based Neurovascular Circuit Characterization for Repair

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