Angiogenesis

Tumors cells need a rich blood supply in order to grow and metastasize. Angiogenesis (Angio-blood, genesis-creation) is the process by which new blood vessels, called capillaries are formed. Capillaries are lined with endothelial cells.

Normal angiogenesis occurs under very tight physiological regulation when stimulators and inhibitors work in balance with each other. Normally the proliferation rate of endothelial cells is very low, with turnover times for these cells exceeding 1000 days.

Exceptions occur in which the angiogenesis process takes approximately 5-8 days. This is seen in wound healing, embryonic development, the monthly growth of the uterine lining in menstruation women, and also in cancer.

The following content, courtesy of University of Brescia, Italy and Associazione Italiana per la Ricerca sul Cancro, provides a brief introduction to the angiognesis process.

 

Special Project Angiogenesis


Angiogenesis: a Brief Introduction

Blood vessels are required to supply oxigen and nutrients and to remove waste products from living tissue.

Angiogenesis is the process of generating new capillary blood vessels.

 


Angiogenesis is fundamental to healing, reproduction, embryonic development. During development, new blood vessels originate from endothelial cell precursors (angioblasts) by a process called VASCULOGENESIS or from pre-existing blood vessels by ANGIOGENESIS. Both processes are mediated by paracrine growth factors.
PARACRINE FACTORS IN THE CONSTRUCTION AND MAINTENANCE OF THE BLOOD VESSELSThe paracrine factors that regulate angiogenesis accomplish their functions by binding to a family of receptor tyrosine kinases that span the cell membrane of the endothelial cells.

1. VASCULOGENESIS begins when VEGF binds to the first of its two receptors, the VEGF-R2 (Flk1) protein. This signal causes the differentiation of mesodermal cells into endothelial cells as well as their proliferation. When the Flk1 genes are knocked out, the mice die at embryonic day 8, and they lack endothelial cells.

2. The formation of the capillary tube occurs when VEGF binds to its second receptor, VEGF-R1 (Flt1). In the absence of this signal, blood vessels fail to form from the endothelial cells, and the mouse dies at embryonic day 8.

3. The next step involves the interactions of the endothelial blood vessel with supporting mesodermal cells. The Angiopoietin-1 factor binds to the Tie2 receptor tyrosine kinase and allows the blood vessel to recruit the peri-endothelial cells that will surround it. These cells become the pericytes and smooth muscle tissue of the blood vessel, and they are important in maintaining the stability of the blood vessels. When the Tie2 genes are knocked out, the blood vessel is readily disrupted, and the mouse embryos die around day 9 and 10.

4. ANGIOGENESIS requires two signals. The combination of Angiopoietin-2 and VEGF causes the loosening of the support cells and the ability of the newly exposed endothelial cells to multiply. Angiopoietin-2 appears to work by blocking the Tie2 signal. While Angiopoietin-2 is widely expressed in the embryo, it appears in the adult specifically in places where angiogenesis is critical: the placenta, the ovary (especially post-ovulation), and the uterus. If the VEGF signal is also being given, angiogenesis occurs. If Angiopoietin-2 inhibits the Tie2 kinase in the absence of VEGF, the endothelium of the blood vessel separates from the peri-endothelial cells, the endothelial cells loose contact with each other, and the blood vessels regress.

A scheme for vessel sprouting (A) and for maturation of the new vessel (B). Vessel structure is maintained by action of Ang1 on Tie2. In A, replacement of Ang1 by Ang2 destabilizes vessel integrity facilitating vessel sprouting in response to VEGF. In B, the new endothelial tubule interacts with surrounding mesenchymal cells in part through Ang1, which acts on endothelial cell Tie2 to promote association of the new tubule with periendothelial cells. The mechanism of this communication is postulated to involve growth factors released from endothelial cells in response to activated Tie2. 
(from: http://www.rndsystems.com/cb/cbfa98/cbfa98a7.html)

The building and remodeling of blood vessels is a critical event in the formation of every organ, and the relationship between the blood vessels and the tissues they serve is tightly balanced between stasis and growth, and regression.

Click here to visualize the vascular structure
enhancement in a day 12.5 mouse embryo.


Click here for a QuickTime movie
of a volume rendered day 14.5 mouse embryo
(860 KB). To down-load a QT viewer click here.


For more Magnetic Resonance Images visit the
Center for In Vivo Microscopy home page 
at Duke University Medical Center

 


The angiogenesis process begins with the degradation of the basement membrane by proteases secreted by activated endothelial cells that will migrate and proliferate, leading to the formation of solid endothelial cell sprouts into the stromal space. Then, vascular loops are formed and capillary tubes develop with formation of tight junctions and deposition of new basement membrane.

The angiogenesis process can be mimicked in vitro after seeding cultured endothelial cells onto suitable substrates (e.g. Matrigel)
Click here for a time-lapse QuickTime movie video of in vitro angiogenesis, it may take few minutes to down-load!
This QT video will not display properly on a PowerMac).
For more informations and nice pictures about endothelial cell morphogenesis on Matrigel take a look at D.S. Grant’shome page at Thomas Jefferson University.
For more images and QT movies connect to The Videomicroscopy Library of the Department of Medical Physiology at Texas A&M University or to the Web site CELLS alive!

In the adult, the proliferation rate of endothelial cells is very low compared to many other cell types in the body. More than 1,000,000,000,000 endothelial cells line the inside of blood vessels and cover an area of 1000 square meters in a 70-Kg adult. The turnover time of these cells can exceed 1000 days. Physiological exceptions in which angiogenesis occurs under tight regulation are found in the female reproductive system and during wound healing. Because angiogenesis is so crucial to physiological functions, it must be carefully controlled in order to maintain health.

The switch to the angiogenic phenotype involves a change in the local equilibrium between positive and negative regulators of the growth of microvessels.

Positive and negative regulators of angiogenesis
Positive regulators Negative regulators
Fibroblast growth factors Thrombospondin-1
Placental growth factor Angiostatin
Vascular endothelial growth factor Interferon alpha
Transforming growth factors Prolactin 16-kd fragment
Angiogenin Metallo-proteinase inhibitors
Interleukin-8 Platelet factor 4
Hepatocyte growth factor Genistein
Granulocyte colony-stimulating factor Placental proliferin-related protein
Platelet-derived endothelial cell growth factor Transforming growth factor beta?
Angiopoietin 1 Endostatin

Abnormal angiogenesis occurs when the body loses its control of angiogenesis, resulting in either excessive or insufficient blood vessel growth. For instance, conditions such as ulcers, strokes, and heart attacks may result from the absence of angiogenesis normally required for natural healing. On the contrary, excessive blood vessel proliferation may favour tumor growth and spreading, blindness, and arthritis.

Take a look at Berkowitz Lab Home Page if you want to know more on angiogenesis as a cause of blindness in diabetic retinopathy and retinopathy of prematurity.

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