Hellmut Augustin Discusses the Angiopoietin-Tie System

Emerging Research Fronts Commentary, December 2011

Hellmut Augustin

Article: Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system

Authors: Augustin, HG;Koh, GY;Thurston, G;Alitalo, K
Journal: NAT REV MOL CELL BIOL, 10 (3): 165-177, MAR 2009
Addresses: Univ Heidelberg, Joint Res Div Vasc Biol, Med Fac Mannheim CBTM, D-6900 Heidelberg, Germany.
Univ Heidelberg, Joint Res Div Vasc Biol, Med Fac Mannheim CBTM, D-6900 Heidelberg, Germany.
DKFZ ZMBH Alliance, German Canc Res Ctr Heidelberg, Heidelberg, Germany.
Korea Adv Inst Sci & Technol, Natl Res Lab Vasc Biol, Taejon 305701, South Korea.
(Addresses have been truncated)

Hellmut Augustin talks with ScienceWatch.com and answers a few questions about this month's Emerging Research Front paper in the field of Molecular Biology & Genetics.

SW: Why do you think your paper is highly cited?

The field of angiogenesis research continues to be among the fastest growing disciplines in contemporary biomedical research. VEGF/VEGF receptor targeting anti-tumor therapies have, within a few years, emerged as the heaviest selling anti-cancer drugs and account today for a significant fraction of the global anti-tumor drug market. Yet, their therapeutic efficacy is limited, resulting in an extension of overall survival within weeks to a few months.

The field of angiogenesis research therefore aims at functionally validating additional targets of the angiogenic cascade that hold promise to combine well with established anti-VEGF/VEGFR therapies to eventually widen the therapeutic window of such established anti-angiogenic therapies. The Angiopoietin/Tie system is a prototypic vessel remodeling and maturation regulating molecular system. The better molecular and functional understanding of this key regulatory system is consequently not just a significant challenge in fundamental basic biomedical research. It also holds promise to lead to the development of novel anti-angiogenic therapies that significantly improve the established anti-angiogenic regimen.

SW: What are the key developments that your review paper covers?

The article focuses on the molecular and functional properties of the Angiopoietin/Tie system. Angiopoietin-1 acts as an agonistic ligand of the vascular receptor tyrosine kinase receptor Tie2. The activation of Tie2 in endothelial cells transduces vessel maturation and quiescence regulating signals. Tie2 is also active in subpopulations of monocytes (TEM, Tie2-positive monocytes) and controls the quiescent state of hematopoietic stem cells in the bone marrow stem cell niche.

Angiopoietin-2 is primarily produced by endothelial cells themselves and acts as context-specific agonist and antagonist of Tie2. As an antagonist, it interferes with Ang-1/Tie2 signaling to induce vessel destabilization and thereby controlling the responsiveness of endothelial cells to exogenous cytokines, including permeability-inducing, inflammation-inducing, and angiogenesis-inducing growth factors. Tie1 signaling is still poorly understood. It is an orphan receptor and controls Ang-1/Tie2 signaling by interacting with Tie2.

SW: Would you summarize the significance of your paper in layman's terms?

Hellmut AugustinVIEW/DOWNLOAD additional figures and descriptions of Hellmut Augustin's work.

Loss of the quiescent properties of the inner lining of blood vessels is involved in some of the most common and some of the deadliest diseases of humans including atherosclerosis, coagulation disorders, stroke, cardiac ischemia, and peripheral arterial diseases. Angiopoietins are growth factors that act on the cells forming the inner lining of blood and lymphatic vessels (endothelial cells). They control the growth and the quiescence properties of endothelial cells.

Angiopoietins therefore play an important role in some of the most important and most devastating human diseases. The better understanding of their function therefore holds great promise to benefit human mankind by leading to the development of novel therapies to some of the most important human diseases.

SW: How did you become involved in this research, and how would you describe the particular challenges, setbacks, and successes that you've encountered along the way?

The field of vascular biology has excited and continues to excite me for more than 20 years. Blood vessels are, in principle, a relatively simple anatomical unit. Yet, their functional complexity is fascinating and will keep us busy for many years to come. The excitement for vascular biology research is also stimulated by the fact that at least 75% of all cases of human death are directly or indirectly related to disturbances of the inner lining of blood vessels.

As such, the better molecular and functional understanding of blood and lymphatic functions has immediate pathophysiological consequences and holds great prospects to lead to the development of novel therapies. For example, the translation of fundamental discoveries in the field of vascular biology has paved the way to novel anti-inflammatory, anti-thrombotic, and anti-angiogenic agents.

As for the specific molecular system covered in the discussed article, the Angiopoietin ligands and their Tie receptors, my interest in these molecules goes back some 10 years ago. I had in 2001 just moved to a company focused on kinases, which had already generated many of the molecular tools necessary to study angiopoietin functions. The angiopoietins had just been discovered few years ago (1996/97) and not much was know about these molecules.

Following the biochemical characterization of angiopoietin binding to Tie2 (Fiedler et al., J. Biol. Chem., 2003), we surprisingly discovered that the antagonistic ligand Ang-2 is not just produced by endothelial cells, but also stored in these cells (Fiedler et al., Blood 2004). As such, Ang-2 can be made rapidly available to control rapid vascular responses in an autocrine manner.

"Angiopoietin/Tie research is still in the early stages and holds many surprises for years to come."

This landmark publication has stimulated much additional work and subsequently led to the discovery of the cellular mechanisms of Ang-2-mediated endothelial cell destabilization (Scharpfenecker et al., J. Cell. Sci., 2005), the uncovering of the key role of Ang-2 as a gatekeeper of inflammatory responses (Fiedler et al., Nat. Med., 2006), the characterization of the unique properties of the Ang-2 promoter (Hegen et al., Arterioscl. Thromb. Vasc. Biol., 2006), the flow-dependent regulation of Ang-2 expression (Goettsch et al., J. Cell. Physiol., 2008), and the identification of the window in which Ang-2 controls tumor vascularization and grow (Nassare et al., Cancer Res., 2009).

The strong transcriptional regulation of Ang-2 expression by endothelial cells also makes Ang-2 one of the best biomarkers of endothelial cell activation (Helfrich et al., Clin. Cancer Res., 2009). In our latest published work, we have unraveled the molecular mechanism of Ang-2-mediated endothelial cell destabilization by Tie2-integrin association and subsequent integrin internalization and degradation (Thomas et al., J. Biol. Chem., 2010).

SW: Where do you see your research leading in the future?

Angiopoietin/Tie research is still in the early stages and holds many surprises for years to come. Presently, we have work in the pipeline showing that the most immature angiogenic endothelial cells are among the most abundant producers of Ang-2. Yet, these cells do not express the Ang-2 receptor Tie2. We identified an alternative receptor pathway through which Ang-2 exerts direct pro-angiogenic functions.

Other work concentrates on the exploitation of Ang-2 as a therapeutic target for anti-tumor therapies. We also have a major interest in the role of Ang/Tie signaling in controlling hematopoietic stem cell functions and in homeostatic maintenance functions in the adult. Along these lines, we study the role of Ang/Tie signaling during tissue regeneration and during ageing of the vascular system. Lastly, Tie1 is a completely unexplored receptor which largely stems from the fact that it is to this day an orphan receptor. We have developed a working model how Tie1 may influence Tie2 signaling as an orphan receptor.

SW: Do you foresee any social or political implications for your research?

This is straightforward fundamental biomedical research with significant translational implications. Yet, I do not see major social or political implications of this work.End

Hellmut G. Augustin, D.V.M., Ph.D.
Professor and Director
Aventis Foundation-endowed Chair for Vascular Biology and Tumor Angiogenesis Medical Faculty Mannheim
Heidelberg University (CBTM)
German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance)
Heidelberg, Germany



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