TY - JOUR T1 - Biology of Vascular Endothelial Growth Factor C in the Morphogenesis of Lymphatic Vessels JF - Frontiers in Biotechnology and Bioengineering Y1 - 2018 A1 - Khushbu Rauniyar A1 - Sawan K Jha A1 - Michael Jeltsch KW - ADAMTS3 KW - CCBE1 KW - growth factor signaling KW - growth factors KW - Lymphatic Vessels KW - lymphedema KW - proteolytic processing KW - Tissue Engineering KW - VEGF receptors KW - VEGF-C AB - Because virtually all tissues contain blood vessels, the importance of hemevascularization has been long recognized in regenerative medicine and tissue engineering. However, the lymphatic vasculature has only recently become a subject of interest. Central to the task of growing a lymphatic network are lymphatic endothelial cells (LECs), which constitute the innermost layer of all lymphatic vessels. The central molecule that directs proliferation and migration of LECs during embryogenesis is Vascular Endothelial Growth Factor-C (VEGF-C). VEGF-C is, therefore, an important ingredient for LEC culture and attempts to (re)generate lymphatic vessels and networks. During its biosynthesis, VEGF-C undergoes a stepwise proteolytic processing, during which its properties and affinities for its interaction partners change. Many of these fundamental aspects of VEGF-C biosynthesis have only recently been uncovered. So far, most - if not all - applications of VEGF-C do not discriminate between different forms of VEGF-C. However, for lymphatic regeneration and engineering purposes, it appears mandatory to understand these differences, since they relate e.g. to such important aspects as biodistribution and receptor activation potential. In this review, we discuss the molecular biology of VEGF-C as it relates to the growth of LECs and lymphatic vessels. However, the properties of VEGF-C are similarly relevant for the cardiovascular system, since both old and recent data show that VEGF-C can have a profound effect on the blood vasculature. VL - 6 UR - https://www.frontiersin.org/articles/10.3389/fbioe.2018.00007/full ER - TY - JOUR T1 - The basis for the distinct biological activities of vascular endothelial growth factor receptor-1 ligands JF - Sci Signal Y1 - 2013 A1 - Anisimov, Andrey A1 - Leppänen, Veli-Matti A1 - Tvorogov, Denis A1 - Zarkada, Georgia A1 - Jeltsch, Michael A1 - Holopainen, Tanja A1 - Kaijalainen, Seppo A1 - Alitalo, Kari KW - PlGF KW - receptor tyrosine kinase KW - Signal Transduction KW - VEGF-B KW - VEGFR-1 AB -

Vascular endothelial growth factors (VEGFs) regulate blood and lymphatic vessel development through VEGF receptors (VEGFRs). The VEGFR immunoglobulin homology domain 2 (D2) is critical for ligand binding, and D3 provides additional interaction sites. VEGF-B and placenta growth factor (PlGF) bind to VEGFR-1 with high affinity, but only PlGF is angiogenic in most tissues. We show that VEGF-B, unlike other VEGFs, did not require D3 interactions for high-affinity binding. VEGF-B with a PlGF-derived L1 loop (B-L1(P)) stimulated VEGFR-1 activity, whereas PlGF with a VEGF-B-derived L1 loop (P-L1(B)) did not. Unlike P-L1(B) and VEGF-B, B-L1(P) and PlGF were also angiogenic in mouse skeletal muscle. Furthermore, B-L1(P) also bound to VEGFR-2 and activated downstream signaling. These results establish a role for L1-mediated D3 interactions in VEGFR activation in endothelial cells and indicate that VEGF-B is a high-affinity VEGFR-1 ligand that, unlike PlGF, cannot efficiently induce signaling downstream of VEGFR-1.

VL - 6 IS - 282 ER -