Angiopoietin growth factors and their possible therapeutic use in the vasculature

The endothelium permeates every organ of the body, and regulates vital processes including oxygen and nutrient transport, tissue fluid homeostasis, blood pressure, inflammation, and angiogenesis. The angiopoietin growth factors (ANG, ANGPT) and the TIE receptor tyrosine kinases (TIE1, TIE2) form an endothelial specific signaling pathway that is a significant regulator of developmental and pathological angiogenesis as well as of vascular homeostasis. Angiopoietin-1 (ANG1) enhances the endothelial barrier function providing vascular stability. In contrast, ANG2 is a proinflammatory growth factor, whose expression increases during hypoxia, microvascular damage, pathological vascular remodeling and in tumor blood vessels, and its expression promotes endothelial destabilization.

Precise regulation of vascular integrity via endothelial cell-cell junctions is critical for cell adhesion, paracellular permeability, vascular growth as well as immune cell trafficking. Increased endothelial permeability and associated inflammation occur in a large number of diseases with different etiology including sepsis, acute respiratory distress syndrome, diabetes and cancer, among others. These diseases present a worldwide health problem as they are difficult to treat. We are focused on attempts to understand the molecular functions of the ANG-TIE signaling system in pathological conditions and in the regulation of normal vascular homeostasis, searching for therapeutic possibilities to modulate endothelial cell functions via the ANG-TIE pathway.

We have discovered a novel mechanism of how angiopoietins activate the TIE receptors specifically at endothelial cell-cell junctions and in cell-matrix contacts, mediating endothelial stability and migration, respectively. A soluble angiopoietin growth factor induces the formation of receptor complexes across the cell-cell junctions, while a matrix-bound angiopoeitin mediates TIE activation at cell-matrix contact sites.

Recently, we showed that blocking ANG2 using therapeutic antibodies reduces tumor growth, angiogenesis, lymphangiogenesis as well as tumor metastasis. Blocking ANG2 inhibited tumor cell homing to the lungs by improving the integrity of endothelial cell-cell junctions in pulmonary capillaries.

Listen to Pipsa Saharinen talking (in Finnish) about her recent findings on angiopoietin-2 signaling in disease http://areena.yle.fi/radio/2542999

Selected publications

Hakanpaa L, Sipila T, Leppanen VM, Gautam P, Nurmi H, Jacquemet G, Eklund L, Ivaska J, Alitalo K, Saharinen P. Endothelial destabilization by angiopoietin-2 via integrin β1 activation. Nat Commun. 2015 Jan 30;6:5962. doi: 10.1038/ncomms6962.

Jeltsch M, Leppänen VM, Saharinen P, Alitalo K. Receptor tyrosine kinase-mediated angiogenesis. Cold Spring Harb Perspect Biol; 5.doi:pii: a009183, 2013.

D’Amico G, Korhonen EA, Anisimov A, Zarkada G, Holopainen T, Hägerling R, Kiefer F, Eklund L, Sormunen R, Elamaa H, Brekken RA, Adams RH, Koh GY, Saharinen P, Alitalo K. Tie1 deletion inhibits tumor growth and improves angiopoietin antagonist therapy. J Clin Invest.;124:824-34, 2014.

Anisimov A, Tvorogov D, Alitalo A, Leppänen VM, An Y, Han EC, Orsenigo F, Gaál EI, Holopainen T, Koh YJ, Tammela T, Korpisalo P, Keskitalo S, Jeltsch M, Ylä-Herttuala S, Dejana E, Koh GY, Choi C, Saharinen P, Alitalo K. Vascular endothelial growth factor-angiopoietin chimera with improved properties for therapeutic angiogenesis. Circulation;127:424-34, 2013.

Tuuminen R, Nykänen AI, Saharinen P, Gautam P, Arnaudova R, Rouvinen E, Tammi R, Rilla K, Krebs R, Lemström KB, MD. Donor simvastatin treatment prevents ischemia-reperfusion and acute kidney injury by preserving microvascular barrier function. American Journal of Transplantation 3: 2019-34, 2013.

Eklund L and Saharinen P. Angiopoietin signaling in the vasculature. Experimental Cell Research 319: 1271-1280, 2013.

Saharinen P1, Eklund L1, Miettinen J, Wirkkala R, Anisimov A, Winderlich M, Nottebaum A, Vestweber D, Deutsch U, Koh GY, Olsen BR and Alitalo K. Angiopoietins assemble distinct Tie2 signaling complexes in endothelial cell-cell and cell-matrix contacts. Nature Cell Biol. 10:527-37, 2008.

Saharinen P, Eklund L, Pulkki K, Bono P and Alitalo, K. VEGF and angiopoietin signaling in tumor angiogenesis and metastasis. Trends Mol Med. 17:347-62, 2011.

Saharinen P, Alitalo K. The yin, the yang, and the angiopoietin-1. J Clin Invest. 121: 2157-9, 2011.

Holopainen T, Saharinen P, D’Amico G, Lampinen A, Eklund L, Sormunen R, Anisimov A, Zarkada G, Lohela M, Heloterä H, Tammela T, Benjamin LE, Ylä-Herttuala S, Leow CC, Koh GY and Alitalo K. Effects of Angiopoietin-2 blocking antibody on endothelial cell-cell junctions and lung metastasis. J Natl Cancer Ins.t 21:461-475. 2012.

Pietilä R, Nätynki M, Tammela T, Kangas J, Pulkki KH, Limaye N, Vikkula M, Koh GY, Saharinen P, Alitalo K, Eklund L. Ligand oligomerization state controls Tie2 receptor trafficking and Angiopoietin-2 ligand specific responses. J Cell Sci. 1: 2212-23, 2012.

Contact

Pipsa Saharinen, PhD, Adjunct professor, Pipsa.Saharinen (at) helsinki.fi
Saharinen P in Pubmed ⊕ Opens in a new tab.

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Wihuri Research Institute

Biomedicum Helsinki
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Director: Kari Alitalo
 
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