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Understanding Angiogenesis in the Eye

Physiological Control of Angiogenesis

Angiogenesis, also called neovascularization, occurs in the healthy body for healing wounds and for restoring blood flow to tissues after injury or insult. In females, angiogenesis also occurs during the monthly reproductive cycle (to generate the endometrium, to form the corpus luteum) and during pregnancy (to build the placenta).

Physiologically, the body controls angiogenesis through a series of "on" and "off" regulatory switches:

• The main "on" switches are known as angiogenesis growth factors (cytokines)
• The main "off switches" are known as endogenous angiogenesis inhibitors

When angiogenic growth factors are produced in excess of angiogenesis inhibitors, the balance is tipped in favor of blood vessel growth. When inhibitors are present in excess of stimulators, angiogenesis is stopped. The normal, healthy body maintains a perfect balance of angiogenesis modulators. In general, angiogenesis is "turned off" by with more inhibitors being produced than stimulators.

In the healthy eye, the regulation of angiogenesis is critical for preserving visual clarity. Normally avascular tissues include the cornea, and the aqueous and vitreous fluids. Neovascularization in the eye leads to vision loss and blindness in a number of significant conditions:

• Pterygium
  Pterygium is a proliferation of fibrovascular tissue on the surface of the eye, associated with ultraviolet light exposure. Within the pterygium are abundantly proliferating blood vessels that promote pannus growth and progression.

• Corneal Neovascularization
  Invasion of new blood vessels into the normally avascular cornea occurs after infection and injury. Corneal neovascularization may be induced by a number of angiogenic growth factors. Basic fibroblast growth factor (bFGF) is normally sequestered within Descemet's membrane and may be mobilized by injury. Inflammatory cells, such as macrophages and monocytes, also contain various angiogenic growth factors and corneal inflammation is a common stimulus for neovascularization.

• Rubeosis Iridis
  Neovascularization in the trabecular meshwork of the anterior chamber is observed in diabetes. New blood vessels obstruct aqueous outflow leading to glaucoma. Diffusible angiogenic factors, such as vascular endothelial growth factor (VEGF), are thought to originate from ischemic retinal tissues and promote neovascularization in the anterior chamber.

• Retinal Neovascularization
  Ischemia is thought to be the primary stimulus for neovascularization in the retina. Local hypoxia leads to upregulation of gene expression for hypoxia inducible factor-1 alpha (HIF-1alpha), which in turn, stimulates production of VEGF. While a number of angiogenic growth factors have been detected in vitreous fluid and retinal tissues, VEGF is regarded as the primary angiogenic factor responsible for retinal neovascularization. VEGF is also known as vascular permeability factor (VPF), and pathological retinal microvessels are leaky. VEGF also serves as a paracrine survival factor for angiogenic endothelial cells. Pericytes, associated with the retinal microvasculature, normally inhibit angiogenesis by secreting activated transforming growth factor-beta (TGF-beta). The loss of pericytes preceding diabetic retinopathy may promote neovascularization by decreasing levels of this endogenous angiogenesis inhibitor.

• Choroidal Neovascularization
  Angiogenesis originating from the choroidal circulation (subretinal neovascularization) is associated with macular edema and degeneration. The angiogenic growth factors, VEGF and FGF are also associated with this process.

• Ocular Tumors
  Both primary and metastatic tumors in the eye are dependent upon angiogenesis for growth and progression. Uveal melanomas have recently been reported to form microvessels in the absence of vascular endothelial cells, but this phenomenon remains controversial. For more information about tumor angiogenesis, please visit our Providers-Oncology site.

List of known angiogenic growth factors

Angiogenin
Angiopoietin-1
Del-1
Fibroblast growth factors: acidic (aFGF) and basic (bFGF)
Follistatin
Granulocyte colony-stimulating factor (G-CSF)
Hepatocyte growth factor (HGF) /scatter factor (SF)
Interleukin-8 (IL-8)
Leptin
Midkine
Placental growth factor (PlGF)
Platelet-derived endothelial cell growth factor (PD-ECGF)
Platelet-derived growth factor-BB (PDGF-BB)
Pleiotrophin (PTN)
Proliferin
Transforming growth factor-alpha (TGF-alpha)
Transforming growth factor-beta (TGF-beta)
Tumor necrosis factor-alpha (TNF-alpha)
Vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF)

The Angiogenesis Process: How Do New Blood Vessels Grow?

The process of angiogenesis occurs as an orderly series of events:

1. Tumors produce and release angiogenic growth factors (proteins) that diffuse into the nearby tissues
2. The angiogenic growth factors bind to specific receptors located on the endothelial cells (EC) of nearby preexisting blood vessels
3. Once growth factors bind to their receptors, the endothelial cells become activated. Signals are sent from the cell's surface to the nucleus. The endothelial cell's machinery begins to produce new molecules including enzymes
4. Enzymes dissolve tiny holes in the sheath-like covering (basement membrane) surrounding all existing blood vessels
5. The endothelial cells begin to divide (proliferate), and they migrate out through the dissolved holes of the existing vessel towards the diseased tissue (tumor)
6. Specialized molecules called adhesion molecules, or integrins (avb3, avb5) serve as grappling hooks to help pull the sprouting new blood vessel sprout forward
7. Additional enzymes (matrix metalloproteinases, or MMP) are produced to dissolve the tissue in front of the sprouting vessel tip in order to accommodate it. As the vessel extends, the tissue is remolded around the vessel
8. Sprouting endothelial cells roll up to form a blood vessel tube
9. Individual blood vessel tubes connect to form blood vessel loops that can circulate blood
10. Finally, newly formed blood vessel tubes are stabilized by specialized muscle cells (smooth muscle cells, pericytes) that provide structural support. Blood flow then begins

Endogenous Angiogenesis Inhibitors

Endogenous inhibitors of angiogenesis are also present in healthy and diseased tissues. These inhibitors are thought to be involved in maintaining the normally avascular state of ocular and other tissues:

Angiostatin (plasminogen fragment)
Antiangiogenic antithrombin III (aaATIII)
Canstatin
Cartilage-derived inhibitor (CDI)
CD59 complement fragment
Endostatin (collagen XVIII fragment)
Fibronectin fragment
Gro-beta
Heparinases
Heparin hexasaccharide fragment
Human chorionic gonadotropin (hCG)
Interferon alpha/beta/gamma
Interferon inducible protein (IP-10)
Interleukin-12 (IL-12)
Kringle 5 (plasminogen fragment)
Metalloproteinase inhibitors (TIMPs)
2-Methoxyestradiol (2-ME)
Pigment epithelial-derived factor (PEDF)
Placental ribonuclease inhibitor
Plasminogen activator inhibitor
Platelet factor-4 (PF4)
Prolactin 16kD fragment
Proliferin-related protein
Retinoids
Tetrahydrocortisol-S
Thrombospondin-1v Transforming growth factor-beta
Tumistatin
Vasculostatin
Vasostatin (calreticulin fragment)

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INHIBITION OF ANGIOGENESIS BY GREEN TEA

Angiogenesis, the origin and development of blood vessels, is an important consideration in the growth of cancerous tumors, since the tumor provokes directed angiogenesis into itself with the end result that the tumor is supplied with oxygen and nutrients. Without angiogenesis, tumors can attain only a small size before becoming self-inhibiting. (The essential point is that effective distribution of oxygen and nutrients by simple diffusion is limited by the size (i.e., volume) of the population of cells). Consumption of tea has been shown to inhibit the growth of several tumor types in animals, including cancers of the lung and esophagus. Drinking tea, especially green tea, is also associated with a lower incidence of human cancer. The mechanisms of cancer inhibition are not known, although several hypotheses have been proposed, including the possibility of inhibition of angiogenesis. ... ... Y. Cao and R. Cao (Karolinska Institute, SE) now report the results of an investigation of the effects of drinking green tea on angiogenesis. The authors investigated both the effects of green tea and of one of its components, epigallocatechin-3-gallate (EGCG). The authors report that EGCG suppresses *endothelial cell growth in vitro (bovine capillary endothelial cells), and the formation of new blood vessels in chick *chorioallantoic membrane. The authors report that drinking green tea significantly prevents corneal neovascularization induced by the potent angiogenic factor VEGF (*vascular endothelial growth factor). The green tea experiments were done with mice, the animals having green tea as the sole drinking fluid. The amount of green tea in the drinking water was 4.69 milligrams per milliliter, containing 708 micrograms per milliliter EGCG, which produces an EGCG plasma concentration in the range 0.1 to 0.3 micromolar, which is similar to levels in humans after drinking 2 or 3 cups of tea. The authors suggest that because the growth of all solid tumors is dependent on angiogenesis, their findings may explain why drinking green tea prevents the growth of a variety of different types of tumor.
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Editor's note: For related material, see the SW Focus Report
"Biology of Cancer: Angiogenesis Inhibition" available at URL
[http://www.scienceweek.com/swfr028.htm].
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Y. Cao and R. Cao: Angiogenesis inhibited by drinking tea.
(Nature 1 Apr 99 398:381)
QY: Yihai Cao [yihai.cao@mtc.ki.se]
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Text Notes:

... ... *endothelial cell: Flat cells forming a layer lining blood vessels, lymphatic vessels, the heart, etc.

... ... *chorioallantoic membrane: An extra-embryonic membrane. In avian embryos such as that of the chicken, it is fused with the egg shell and is crucial for chick embryonic development.

... ... *vascular endothelial growth factor: (vascular permeability growth factor; vasculotropin)
A protein produced by epithelial and other types of cells, active in angiogenesis and endothelial cell growth.