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Proteolytic Cleavages in the VEGF Family: Generating Diversity among Angiogenic VEGFs, Essential for the Activation of Lymphangiogenic VEGFs
SIMPLE SUMMARY: Vascular endothelial growth factors (VEGFs) regulate the growth of blood and lymphatic vessels. Some of them induce the growth of blood vessels, and others the growth of lymphatic vessels. Blocking VEGF-A is used today to treat several types of cancer (“antiangiogenic therapy”). Howe...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926383/ https://www.ncbi.nlm.nih.gov/pubmed/33672235 http://dx.doi.org/10.3390/biology10020167 |
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author | Künnapuu, Jaana Bokharaie, Honey Jeltsch, Michael |
author_facet | Künnapuu, Jaana Bokharaie, Honey Jeltsch, Michael |
author_sort | Künnapuu, Jaana |
collection | PubMed |
description | SIMPLE SUMMARY: Vascular endothelial growth factors (VEGFs) regulate the growth of blood and lymphatic vessels. Some of them induce the growth of blood vessels, and others the growth of lymphatic vessels. Blocking VEGF-A is used today to treat several types of cancer (“antiangiogenic therapy”). However, in other diseases, we would like to increase the activity of VEGFs. For example, VEGF-A could generate new blood vessels to protect from heart disease, and VEGF-C could generate new lymphatics to counteract lymphedema. Clinical trials are testing the latter concept at the moment. Because VEGF-C and VEGF-D are produced as inactive precursors, we propose that novel drugs could also target the enzymatic activation of VEGF-C and VEGF-D. However, because of the delicate balance between too much and too little vascular growth, a detailed understanding of the activation of the VEGFs is needed before such concepts can be converted into safe and efficacious therapies. ABSTRACT: Specific proteolytic cleavages turn on, modify, or turn off the activity of vascular endothelial growth factors (VEGFs). Proteolysis is most prominent among the lymphangiogenic VEGF-C and VEGF-D, which are synthesized as precursors that need to undergo enzymatic removal of their C- and N-terminal propeptides before they can activate their receptors. At least five different proteases mediate the activating cleavage of VEGF-C: plasmin, ADAMTS3, prostate-specific antigen, cathepsin D, and thrombin. All of these proteases except for ADAMTS3 can also activate VEGF-D. Processing by different proteases results in distinct forms of the “mature” growth factors, which differ in affinity and receptor activation potential. The “default” VEGF-C-activating enzyme ADAMTS3 does not activate VEGF-D, and therefore, VEGF-C and VEGF-D do function in different contexts. VEGF-C itself is also regulated in different contexts by distinct proteases. During embryonic development, ADAMTS3 activates VEGF-C. The other activating proteases are likely important for non-developmental lymphangiogenesis during, e.g., tissue regeneration, inflammation, immune response, and pathological tumor-associated lymphangiogenesis. The better we understand these events at the molecular level, the greater our chances of developing successful therapies targeting VEGF-C and VEGF-D for diseases involving the lymphatics such as lymphedema or cancer. |
format | Online Article Text |
id | pubmed-7926383 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-79263832021-03-04 Proteolytic Cleavages in the VEGF Family: Generating Diversity among Angiogenic VEGFs, Essential for the Activation of Lymphangiogenic VEGFs Künnapuu, Jaana Bokharaie, Honey Jeltsch, Michael Biology (Basel) Review SIMPLE SUMMARY: Vascular endothelial growth factors (VEGFs) regulate the growth of blood and lymphatic vessels. Some of them induce the growth of blood vessels, and others the growth of lymphatic vessels. Blocking VEGF-A is used today to treat several types of cancer (“antiangiogenic therapy”). However, in other diseases, we would like to increase the activity of VEGFs. For example, VEGF-A could generate new blood vessels to protect from heart disease, and VEGF-C could generate new lymphatics to counteract lymphedema. Clinical trials are testing the latter concept at the moment. Because VEGF-C and VEGF-D are produced as inactive precursors, we propose that novel drugs could also target the enzymatic activation of VEGF-C and VEGF-D. However, because of the delicate balance between too much and too little vascular growth, a detailed understanding of the activation of the VEGFs is needed before such concepts can be converted into safe and efficacious therapies. ABSTRACT: Specific proteolytic cleavages turn on, modify, or turn off the activity of vascular endothelial growth factors (VEGFs). Proteolysis is most prominent among the lymphangiogenic VEGF-C and VEGF-D, which are synthesized as precursors that need to undergo enzymatic removal of their C- and N-terminal propeptides before they can activate their receptors. At least five different proteases mediate the activating cleavage of VEGF-C: plasmin, ADAMTS3, prostate-specific antigen, cathepsin D, and thrombin. All of these proteases except for ADAMTS3 can also activate VEGF-D. Processing by different proteases results in distinct forms of the “mature” growth factors, which differ in affinity and receptor activation potential. The “default” VEGF-C-activating enzyme ADAMTS3 does not activate VEGF-D, and therefore, VEGF-C and VEGF-D do function in different contexts. VEGF-C itself is also regulated in different contexts by distinct proteases. During embryonic development, ADAMTS3 activates VEGF-C. The other activating proteases are likely important for non-developmental lymphangiogenesis during, e.g., tissue regeneration, inflammation, immune response, and pathological tumor-associated lymphangiogenesis. The better we understand these events at the molecular level, the greater our chances of developing successful therapies targeting VEGF-C and VEGF-D for diseases involving the lymphatics such as lymphedema or cancer. MDPI 2021-02-23 /pmc/articles/PMC7926383/ /pubmed/33672235 http://dx.doi.org/10.3390/biology10020167 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Künnapuu, Jaana Bokharaie, Honey Jeltsch, Michael Proteolytic Cleavages in the VEGF Family: Generating Diversity among Angiogenic VEGFs, Essential for the Activation of Lymphangiogenic VEGFs |
title | Proteolytic Cleavages in the VEGF Family: Generating Diversity among Angiogenic VEGFs, Essential for the Activation of Lymphangiogenic VEGFs |
title_full | Proteolytic Cleavages in the VEGF Family: Generating Diversity among Angiogenic VEGFs, Essential for the Activation of Lymphangiogenic VEGFs |
title_fullStr | Proteolytic Cleavages in the VEGF Family: Generating Diversity among Angiogenic VEGFs, Essential for the Activation of Lymphangiogenic VEGFs |
title_full_unstemmed | Proteolytic Cleavages in the VEGF Family: Generating Diversity among Angiogenic VEGFs, Essential for the Activation of Lymphangiogenic VEGFs |
title_short | Proteolytic Cleavages in the VEGF Family: Generating Diversity among Angiogenic VEGFs, Essential for the Activation of Lymphangiogenic VEGFs |
title_sort | proteolytic cleavages in the vegf family: generating diversity among angiogenic vegfs, essential for the activation of lymphangiogenic vegfs |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926383/ https://www.ncbi.nlm.nih.gov/pubmed/33672235 http://dx.doi.org/10.3390/biology10020167 |
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