Ординатура / Офтальмология / Учебные материалы / Retinal Vascular Disease Joussen Springer

Lutz L. Hansen, MD

Department of Ophthalmology, University of

Freiburg, Killianstrasse 5, 79106 Freiburg, Germany

Heinrich Heimann, MD

St. Paul’s Eye Unit, Royal Liverpool University Hospital, Prescot Street, Liverpool, L7 8XP, UK

Horst Helbig, MD

Department of Ophthalmology, University of

Regensburg, Franz-Josef-Strauss-Allee 11

93053 Regensburg, Germany

Hans Hoerauf, MD

Department of Ophthalmology, University of

Göttingen, Robert-Koch-Str. 40, 37075 Göttingen

Germany

John J. Huang, MD

Yale Eye Center, 330 Cedar Street, P.O. Box 208061 New Haven, CT 06520-8061, USA

Claudia Jandeck, MD

Department of Ophthalmology

Campus Benjamin Franklin

Charit´e Universitätsmedizin Berlin, Germany

Antonia M. Joussen, MD, PhD

Department of Ophthalmology, University of

Düsseldorf, Moorenstr. 5, 40225 Düsseldorf

Germany

Bernhard Jurklies, MD

Department of Vitreoretinal Surgery, University of

Essen, Hufelandstrasse 55, 45122 Essen, Germany

William G. Kaelin, Jr, MD

Dana-Farber Cancer Institute, 44 Binney Street Mayer 457, Boston, MA 02115, USA

C. Ronald Kahn, MD, PhD

Joslin Diabetes Center, One Joslin Place, Boston

MA 02215, USA

Barrett Katz, MD, MBA

Weill Medical College, Cornell University, New York-Presbyterian Hospital, 525 East 68th St., New York, NY 10021, USA; and Fovea Pharmaceuticals SA, 12 rue Jean-Antoine de Baif, 75013 Paris, France

Timothy S. Kern, PhD

Department of Medicine, Division of Clinical and Molecular Endocrinology, Center for Diabetes Research, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106-4951, USA

George L. King, MD

Joslin Diabetes Center, Harvard Medical School One Joslin Place, Boston, MA 02215, USA

Bernd Kirchhof, MD

Department of Vitreoretinal Surgery, Center for Ophthalmology, University of Cologne, Joseph- Stelzmann-Strasse 9, 50931 Cologne, Germany

Todd Klesert, MD, PhD

Wilmer Eye Institute, Johns Hopkins Hospital 600 N. Wolfe Street, Baltimore, MD 21287, USA

Ina Kötter, MD

Department of Internal Medicine, University of

Tübingen, Ottfried-Müller-Str. 10, 72076 Tübingen

Germany

Ferenc Kuhn, MD, PhD

Helen Keller Foundation for Research and Education, University of Alabama at Birmingham 1201 11th Avenue South, Birmingham, AL 35205 USA

Michael Lai, MD, PhD

Associated Retinal Consultants, William Beaumont Hospital Medical Building, Suite 632, 3535 W. Thirteen Mile Road, Royal Oak, MI 48073, USA

Gabriele E. Lang, MD

Department of Ophthalmology, University of Ulm

Prittwitzstr. 43, 89075 Ulm, Germany

Michael Larsen, MD, DMSc

Department of Ophthalmology, Herlev Hospital

University of Copenhagen, Copenhagen, Denmark

Susan Lightman, FRCP, FRCOphth, PhD

Department of Clinical Ophthalmology, Institute of Ophthalmology, Moorfields Eye Hospital London City Road, London, EC1V 2PD, UK

Gerard A. Lutty, PhD

The Wilmer Eye Institute, Johns Hopkins Hospital

600 N. Wolfe Street, Baltimore, MD 21287-9115

USA

Friederike Mackensen, MD

Department of Ophthalmology, University of

Heidelberg, Im Neuenheimer Feld 400

69120 Heidelberg, Germany

Gottfried Martin, PhD

Department of Ophthalmology, University of

Freiburg, Killianstrasse 5, 79106 Freiburg, Germany

Trevor J. McFarland, BS

Casey Eye Institute, Oregon Health and Science

University, 3375 SW Terwilliger Blvd., Portland

OR 97239, USA

Viktoria Mester, MD

General Authority of Health Services, for the Emirates of Abu Dhabi Middle Region, Mafraq Hospital, PO Box 2951, Abu Dhabi, United Arab Emirates

Daniel W. Miller, MD

Department of Ophthalmology, University of

Heidelberg, Im Neuenheimer Feld 400

69120 Heidelberg, Germany

Susanne Mohr, PhD

Department of Ophthalmology, Biomedical Research Building, 434, School of Medicine, Case Western Reserve University, 10900 Euclid Ave. Cleveland, OH 44106 – 4951, USA

Robert Morris, MD

Helen Keller Foundation for Research and Education, University of Alabama at Birmingham 1201 11th Avenue South, Birmingham, AL 35205, USA

Quan Don Nguyen, MD, MSc

The Wilmer Eye Institute, The Johns Hopkins

Hospital, 600 N. Wolfe Street, Baltimore, MD 21287

USA

Annelii Ny, PhD

Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KULeuven, Campus Gasthuisberg Herestraat 49, 3000, Leuven, Belgium

Narciss Okhravi, BSc, FRCOphth, PhD

Department of Clinical Ophthalmology, Institute of Ophthalmology, Moorfields Eye Hospital London City Road, London, EC1V 2PD, UK

Björn Padge, MD

Department of Ophthalmology, St. Franziskus-

Hospital, Hohenzollernring 74, 48415 Münster

Germany

Daniel Pauleikhoff, MD

Department of Ophthalmology, St. Franziskus-

Hospital, Hohenzollernring 74, 48415 Münster

Germany

Brett E. Phillips, PhD

Cellular & Molecular Physiology, Penn State College

of Medicine, 500 University Drive, Hershey

PA 17033, USA

Vasiliki Poulaki, MD, PhD

Massachusetts Eye and Ear Infirmary, Harvard

Medical School, 243 Charles Street, Boston

MA 02114, USA

Polly Quiram, MD, PhD

Associated Retinal Consultants, William Beaumont Hospital Medical Building, Suite 632, 3535 W. Thirteen Mile Road, Royal Oak, MI 48073, USA

Nastaran Rafiei, MD

Repartment of Neurology, University of California –

Irvine California, USA

Narsing A. Rao, MD

Department of Ophthalmology, Doheny Eye Institute

University of Southern California, Los Angeles

California, USA

Johann Roider, MD

Department of Ophthalmology, University of

Schleswig-Holstein, Kiel Campus, Hegewischstr. 2

24105 Kiel, Germany

James T. Rosenbaum, MD

Casey Eye Institute, Oregon Health & Science

University, 3375 SW Terwilliger Blvd., Portland

OR 97239-4146, USA

Florian Rüfer, MD

Department of Ophthalmology, University of

Schleswig-Holstein, Kiel Campus, Hegewischstr. 2

24105 Kiel, Germany

Stephen J. Ryan, MD

Doheny Eye Institute, University of Southern

California, 1450 San Pablo Street, Los Angeles

CA 90033, USA

Srinivas R. Sadda, MD

Department of Ophthalmology, Doheny Eye

Institute, University of Southern California

1450 San Pablo Street, Los Angeles, CA 90033

USA

Andrew P. Schachat, MD

The Cole Eye Institute, The Cleveland Clinic

Foundation, 9500 Euclid Avenue, Cleveland

Ohio 44195 USA

Torsten Schlote, MD, PhD

Augenzentrum der Klinik Pallas, Louis-Giroud- Strasse 20, 4600 Olten, Switzerland

Leopold Schmetterer, PhD

Department of Clinical Pharmacology, Währinger

Gürtel 18 – 20, 1090 Vienna, Austria

Michael Scholz, PhD

Institute of Anatomy, University of Erlangen

Universitätsstrasse 19, 91054 Erlangen, Germany

Andreas Schüler, MD

Augenklinik Universitätsallee, Parkallee 301/

Universitätsallee, 28213 Bremen, Germany

Ingrid U. Scott, MD, MPH

Department of Ophthalmology, Penn State College of Medicine, 500 University Drive, HU19, Hershey PA 17033-0850, USA

Nilanjana Sengupta, PhD

University of Florida, Academic Research Bldg.

ARB5-250, 1600 SW Archer Rd, Gainesville

FL 32618, USA

Syed Mahmood Shah, MD

The Wilmer Eye Institute, The Johns Hopkins

Hospital, 600 N. Wolfe Street, Baltimore, MD 21287

USA

Carol L. Shields, MD

Ocular Oncology Service, Department of Ocular Oncology, Wills Eye Hospital, 840 Walnut Street Philadelphia, PA 19107; Thomas Jefferson University, Philadelphia, Pennsylvania, USA

Jerry A. Shields, MD, PhD

Ocular Oncology Service, Department of Ocular Oncology, Wills Eye Hospital, 840 Walnut Street Philadelphia, PA 19107; Thomas Jefferson University, Philadelphia, Pennsylvania, USA

Sobha Sivaprasad, MS, DNB, FRCS

Department of Clinical Ophthalmology, Institute of Ophthalmology, Moorfields Eye Hospital London City Road, London, EC1V 2PD, UK

Lois E.H. Smith, MD, PhD

Department of Ophthalmology, Children’s Hospital

Harvard Medical School, 300 Longwood Avenue

Boston, MA 02115, USA

Wael Soliman, MD

Department of Ophthalmology, Herlev Hospital

University of Copenhagen, Herlev Ringvej 75

2730 Herlev, Denmark

Alan W. Stitt, PhD

Department of Ophthalmology, Queen’s University

of Belfast, Institute of Clinical Science, Royal

Victoria Hospital, Belfast, BT12 6BA, Northern

Ireland, UK

J. Timothy Stout, MD, PhD

Casey Eye Institute, 3375 SW Terwilliger Blvd. Portland, OR 97237-4197, USA

Nicole Stübiger, MD

Department of Ophthalmology, University of

Tübingen, Schleichstr. 12 – 16, 72076 Tübingen

Germany

Jennifer K. Sun, MD

Section of Eye Research, Joslin Diabetes Center Harvard Medical School, One Joslin Place, Boston MA 02215, USA

Kiyoshi Suzuma, MD

Department of Ophthalmology and Visual Sciences

Graduate School of Medicine, Kyoto University

54 Kawaracho Shogoin, Sakyo-ku Kyoto 606-8507

Japan

Homayoun Tabandeh, MD, MS, FRCP, FRCOphth

Retina-Vitreous Associates Medical Group

8641 Wilshire Blvd., #210 Beverly Hills, CA 90211

USA

Ernst R. Tamm, MD

Institute of Human Anatomy and Embryology

University of Regensburg, Universitätsstr. 31,

93053 Regensburg, Germany

Eric Tourville, MD

Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University, 600 N. Wolfe Street, Baltimore, MD 21287, USA

Michael T. Trese, MD

Associated Retinal Consultants, William Beaumont Hospital Medical Building, Suite 344, 3535 W. Thirteen Mile Road, Royal Oak, MI 48073, USA

Heather D. VanGuilder, BSc

Ophthalmology C4800 H166, Penn State College of

Medicine, 500 University Drive, Hershey, PA 17033

USA

Jan van Meurs, MD, PhD

The Rotterdam Eye Hospital, Schiedamsevest 180 3011, BH Rotterdam, The Netherlands

Alexander Walsh, MD

Department of Ophthalmology, Doheny Eye Institute, University of Southern California, 1450 San Pablo Street, Los Angeles, CA 90033, USA

Achim Wessing, MD

Horster Strasse 115, 45968 Gladbeck, Germany

Ute Wiehler, MD

Department of Ophthalmology, University of

Heidelberg, Im Neuenheimer Feld 400,

69120 Heidelberg, Germany

Sebastian Wolf, MD, PhD

Department of Ophthalmology, Inselspital

University of Bern, 3010 Bern, Switzerland

Manfred Zierhut, MD

Department of Ophthalmology, University of

Tübingen, Schleichstr. 12 – 16, 72076 Tübingen

Germany

Core Messages

The retinal vasculature is arranged in a threedimensional network. Abnormalities of retinal circulation are key pointers to retinal dysfunction and disease and may highlight perturbations of systemic circulation such as diabetes, hypertension and sickle cell disease

There are specific responses of the retina and its vasculature to stress and disease, combining hemodynamic changes, oxygen saturation changes, occlusion and ischemia, and repair and remodeling. Furthermore, there are specific reactions to trauma, radiational damage, drug toxicity, and inflammation

1.1Anatomical Organization of the Retinal Vasculature

1.1.1 Microvascular Arrangement

The densely cellular retina with its intricate arrangement of neurons requires highly specialized circulations to meet its demanding metabolic requirements without compromising its extracellular space, which is a highly defined microenvironment conducive to neurotransmission, phototransduction and the complex interaction of metabolites, growth factors and vasoactive agents. The retinal circulation, which supplies the inner retina, is observed ophthalmoscopically as a regular geometrically arranged network of vessels and their three-dimensional complexity reflects the cellular density of the retinal neuropile. The caliber of directly viewed vessels is determined by the size of the red cell column, as the vessel walls and peripheral plasma layer are virtually transparent. The vessels accordingly appear wider during fluorescein angiography as dye mixes with the luminal plasma. As the vessel walls sclerose with age, stress or disease processes they become visible, due to reflected light on ophthalmoscopy, and obscure the red cell column to varying degrees. Abnormalities of the retinal circulation are key pointers to retinal dysfunction and disease and frequently highlight perturbations of the systemic circulation, e.g., diabetes, hypertension, and sickle cell disease.

The central retinal artery is a direct branch of the ophthalmic artery arising from bifurcations adjacent

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Fig. 1.1. Normal right fundus. M macula

to the optic disk to form a unique, intraretinal, endartery microvascular system (Fig. 1.1). The development of the blood supply is intimately linked with embryological progress of the neural retina and other intraocular structures, such as the lens [29], developing a complex network in unison with oxygen demands and local tissue gradients of vasoactive growth factors such as vascular endothelial growth factor (VEGF) [7, 27, 36]. Oxygen tension in the mammalian inner retina has been identified as a key regulator of retinal cell differentiation and microvas-

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I Pathogenesis of Retinal Vascular Disease

cular permeability, growth and survival by altering expression of VEGF [2, 23, 25], controlled, in part, by cellular oxygen and activation of the transcription factor hypoxia inducible factor-1 (HIF-1) [9]. In the mature retinal microvasculature, this oxygenregulated control of capillary density is well illustrated by the appearance of a so-called “capillary-free zone” adjacent to arterial walls where oxygen tension is high and local expression of VEGF is low [8] (Figs. 1.2, 1.3).

Cilioretinal arteries may also contribute to the retinal circulation and these originate from posterior ciliary vessels. The cilioretinal system typically supplies the macular region or part of the macular region of the neuropile and it is notable that these vessels adopt a “retinal structure” typified by tight junctions and barrier properties (Fig. 1.4).

Branch retinal “arteries” lack an internal elastic lamina and, anatomically speaking, are arterioles. These arterioles are ~200 μm in diameter and in the peripheral retina bifurcate to third and fourth orders and finally to pre-capillary arterioles (Fig. 1.5) that lack a pre-capillary sphincter that is a feature of the rodent retinal vasculature. However, this arrangement is altered in the central retina where small precapillary arterioles emerge abruptly from the larger radial arteries. These vessels merge seamlessly into highly complex capillary networks consisting of two

Fig. 1.2. Right fundus – central retinal artery obstruction: immediate periarteriolar retina survives (arrows) due to arteriolar oxygen “leak” and is transparent; ischemic retina is edematous and opaque

Fig. 1.3. Trypsin digest preparation shows the capillary-free zone adjacent to a retinal artery (arrow)

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Fig. 1.10. Electron micrograph of an arteriovenous crossing from the retinal vasculature of a dog reveals the shared basement membrane (arrow) and juxtaposition of the vascular smooth muscle of the artery (A) and the endothelium of the vein (V)

Fig. 1.11. The abluminal plasma membranes of the retinal vascular endothelium are covered by elaborate arrays of caveolae (arrows), in contrast to the luminal surface, where these structures are relatively sparse and occur either singly or in small groups. E endothelium, L lumen

extracellular space into the retinal circulation. The endothelial cells of the retinal vessels form a continuous, non-fenestrated monolayer, with each cell being fused to juxtaposed neighbors by zonulae occludens tight junctions that maintain barrier function (Fig. 1.12a, b). This property of the intraretinal circulation is structurally and functionally analogous to the blood brain barrier and is thought to be maintained in part by the surrounding neuroglia [15] and pericytes that promote tight junction integrity and the non-fenestrated phenotype of the retinal vascular endothelium [3]. When these cell relationships are disrupted as in some pathological situations (diabetes, radiation-retinopathy), the barrier properties of the retinal vessels may be compromised or lost. In such situations the endothelial cells can lose tight-junction integrity and may even assume a fenestrated phenotype (see later in chapter).

In regard to cell turnover and the cell cycle, the endothelial cells and pericytes of the retinal circulation represent highly stable populations with the vast majority of the cells in G0 phase of the cell cycle; however, they are able to reenter the cycle in response to vascular injury, cell loss or angiogenic stimuli. Under physiological conditions there is a low but measurable labeling index with DNA precursors such as tritiated thymidine (3H-T), reflecting an ongoing need for cell replacement. In rats this index is 0.33 % for retinal endothelial cells and 0.16 % for pericytes [31] (Fig. 1.13). Interestingly in diabetes, where there is accelerated vascular cell death [21], the endothelial cells respond by an increased turnover (3H-T labeling index 0.91 %), although the pericytes remained quiescent.

E

Fig. 1.13. Autoradiogram of a retinal digest from a rat that received a continuous infusion of 3H-thymidine for 8 days. The nuclei of two neighboring endothelial cells (E) within the same vessel are heavily decorated with silver grains

1.2Responses of the Retina and Its Vasculature to Stress and Disease: Histological and Pathological Consequences

1.2.1 Hemodynamic Changes

Increased arteriolar intraluminal pressure induces reactive vessel narrowing probably by stretch-acti- vated calcium channels[22]. This may be focal in nature and have a downstream influence on arterioles and capillary beds. Severe and sustained hypertension and associative arteriolar narrowing (Fig. 1.14) may lead to occlusion of pre-arteriolar

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