Vascular Endothelial Growth Factor

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Crystal structure of Vammin, a VEGF-F made from snake venom

The vascular endothelial growth factors (the English abbreviation VEGF for Vascular Endothelial Growth Factor is also common in German) are a group of important signaling molecules that are mainly used in vasculogenesis ( de novo formation of the embryonic blood vessel system and lymphatic system ) as well as in angiogenesis and the Lymphangiogenesis (the growth of new blood or lymph vessels from existing vessels) unfolds its effect. As the name implies, this factor mainly stimulates the cell layer directly adjacent to the blood (the vascular endothelium ), but also has effects on other cells (e.g. stimulation of the migration of monocytes and macrophages ). In vitro , VEGF stimulates the division and migration of endothelial cells. Five different VEGFs are known in mammals (AD as well as PlGF), each of which can occur in different forms, which are generated by alternative splicing and post-translational modifications .

The term VEGF describes a family of proteins that have different properties. VEGF-A was first discovered, then the factors VEGF-B and PlGF (Placental Growth Factor) as well as VEGF-C and VEGF-D (both important for the formation of lymphatic vessels ) were discovered. The related viral homologues (VEGF-E) and the VEGF-F present in snake venom also exist.

VEGF-A

VEGF-A is found in all vascularized tissues and is believed to be necessary for vascular homeostasis . The gene coding for VEGF-A can produce different variants of the protein of different lengths by alternative splicing . So far, the variants VEGF-A 121 , VEGF-A 138 , VEGF-A 145 , VEGF-A 162 , VEGF-A 165 , VEGF-A 165b , VEGF-A 189 and VEGF-A 206 have been described in humans (the numbers correspond to the number of amino acids in the respective protein).

These proteins only differ in their short domains at the C-terminus, which, however, has a major influence on their biological function and controls their interaction with heparan sulfates and the co-receptor Neuropilin.

function

All members of the VEGF family cause a cellular response by binding to a tyrosine kinase , the VEGF receptor (VEGFR), and thus transmitting the extracellular signal inside the cell. There are three receptors (VEGFR 1-3), with different affinities being observed. VEGF-A only binds to receptor types 1 and 2, while PlGF and VEGF-B only bind to receptor type 1 and VEGF-C and VEGF-D only bind to receptors type 2 and 3. VEGF-E and F both to type 2 receptors. The receptors dimerize after binding VEGF and then phosphorylate each other. They become active and forward the signal .

The production of VEGF is stimulated when cells are not receiving enough oxygen . In this case, cells produce hypoxia-induced factors that lead to the release of VEGF and ultimately to angiogenesis . This was elucidated on cell lines.

VEGF promotes the production of nitric oxide (NO) in the vessel wall , which in turn leads to vasodilation and a drop in blood pressure .

Medical importance

An increased expression of VEGF-A is found in a number of tumors in which it increases the permeability of the blood vessels and thus opens the blood-tumor barrier . In addition, the interaction between VEGF and the VEGF receptor in the kidney plays an important role in the development of the organ and in maintaining the filtration barrier .

The monoclonal antibody bevacizumab binds to VEGF-A and thus inhibits the formation of new blood vessels (angiogenesis). Bevacizumab has been used successfully against colon cancer , lung cancer and breast cancer in Phase III trials . In Phase II studies, bevacizumab was used in the treatment of pancreatic cancer , kidney cancer, and prostate cancer . Side effects are bleeding , ulcers in the gastrointestinal tract and kidney damage with high blood pressure and proteinuria (protein in the urine). Ranibizumab is a fragment of the same antibody. It is used to treat wet macular degeneration , an eye disease that often leads to blindness and which is often associated with the formation of new blood vessels. Bevacizumab is also used off label for this indication .

The tyrosine kinase inhibitors sunitinib , sorafenib , ramucirumab and vatalanib also inhibit the VEGF receptor. Sunatinib and sorafenib are used in the treatment of advanced kidney cancer, vatalanib in the treatment of colon cancer, and ramucirumab in the treatment of gastric cancer .

VEGF Trap is a recombinant fusion protein in which the binding domain of the soluble VEGF receptor to the Fc fragment of immunoglobulin G is combined. VEGF Trap binds all isoforms of VEGF-A. It is currently being tested in cancer treatment as well as in the treatment of wet macular degeneration.

Pegaptanib is an aptamer that specifically binds to VEGF-A. It is approved for the treatment of wet macular degeneration.

In the kidney corpuscle , VEGF is responsible for maintaining the integrity of the fenestrated capillary endothelial cells . During pregnancy , VEGF can be inhibited by the soluble VEGF receptor ( sFlt1 ). This is formed in the placenta and enters the kidney with the blood. The result of the reduced VEGF activity is swelling of the endothelial cells in the kidney corpuscle, which ultimately leads to the clinical picture of preeclampsia . In cancer patients, anti-VEGF treatment can lead to proteinuria and thrombotic microangiopathy .

Web links

Individual evidence

  1. ↑ S yla-Herttuala, TT Rissanen, I Vajanto, J Hartikainen: Vascular endothelial growth factors: biology and current status of clinical applications in cardiovascular medicine . In: J Am Coll Cardiol . , 2007 Mar 13, 49 (10), pp. 1015-1026, PMID 17349880 .
  2. ^ S. Cebe Suarez, M. Pieren u. a .: A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2. In: Cellular and Molecular Life Sciences. 63, 2006, pp. 2067-2077, doi: 10.1007 / s00018-006-6254-9 .
  3. ↑ KM Mohamed, A. Le u. a .: Correlation between VEGF and HIF-1alpha expression in human oral squamous cell carcinoma. In: Experimental and molecular pathology , Volume 76, Number 2, April 2004, pp. 143-152, doi: 10.1016 / j.yexmp.2003.10.005 , PMID 15010293 .
  4. ↑ D. Shweiki, A. Itin et al. a .: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. In: Nature Volume 359, Number 6398, October 1992, pp. 843-845, doi: 10.1038 / 359843a0 , PMID 1279431 .
  5. ↑ Timothy D. Henry et al .: The VIVA Trial: Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis . In: Circulation . No. 107 , 2003, p. 1359-1365 ( ahajournals.org ).
  6. ↑ Hassane Izzedine et al .: Angiogenesis Inhibitor Therapies: Focus on Kidney Toxicity and Hypertension . In: American Journal of Kidney Diseases . No. 50 , 2007, p. 203-218 ( ajkd.org ).
  7. ↑ Xiaolei Zhu et al .: Risks of Proteinuria and Hypertension With Bevacizumab, an Antibody Against Vascular Endothelial Growth Factor: Systematic Review and Meta-Analysis . In: American Journal of Kidney Diseases . No. 49 , 2007, p. 186-193 ( ajkd.org ).
  8. ↑ J. Holash, S. Davis, et al. a .: VEGF-Trap: a VEGF blocker with potent antitumor effects. In: Proceedings of the National Academy of Sciences of the United States of America Volume 99, Number 17, August 2002, pp. 11393-11398, doi: 10.1073 / pnas.172398299 , PMID 12177445 , PMC 123267 (free full text).
  9. ↑ A. Dowlati: Hunting and trapping the vascular endothelial growth factor. In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology , Volume 28, Number 2, January 2010, pp. 185-187, doi: 10.1200 / JCO.2009.25.4359 , PMID 19949005 .
  10. ↑ PK Kaiser: Vascular endothelial growth factor Trap-Eye for diabetic macular edema. In: The British journal of ophthalmology Volume 93, Number 2, February 2009, pp. 135-136, doi: 10.1136 / bjo.2008.144071 , PMID 19174397 .
  11. ↑ Isaac E. Stillman, S. Ananth Karumanchi: The Glomerular Injury of Preeclampsia . In: J Am Soc Nephrol . No. 18 , 2007, p. 2281-2284 , PMID 17634433 .
  12. ↑ Roncone D et al .: Proteinuria in a patient receiving anti-VEGF therapy for metastatic renal cell carcinoma . In: Nat Clin Pract Nephrol . No. 3 (5) , 2007, pp. 287-293 , PMID 17457362 .
  13. ↑ Izzedine H et al .: Thrombotic microangiopathy and anti-VEGF agents . In: Nephrol Dial Transplant . No. 22 , 2007, p. 1481-1482 ( oxfordjournals.org ).