Evidence for the interaction of fibroblast growth factor-2 with the lymphatic endothelial cell marker LYVE-1

Abstract

• FGF2 is able to directly interact with LYVE-1 and glycosylation of LYVE-1 is important for the interaction with FGF2.• LYVE-1 inhibits FGF2-dependent lymphangiogenesis and FGF2 modulates LYVE-1's endogenous expression and reverses the effect of TNF␤.LYVE-1 (lymphatic vessel endothelial hyaluronan receptor-1) is a homolog of the hyaluronan receptor CD44, and one of the most widely used markers of lymphatic endothelial cells in normal and tumor tissues. However, the physiologic role of LYVE-1 in the lymphatic system still remains unclear. It is well established that fibroblast growth factor 2 (FGF2) induces lymphangiogenesis. Based on the known interaction between FGF2 and CD44 and based on the structural similarity of CD44 and LYVE-1, we investigated whether FGF2 might interact with LYVE-1. We found that FGF2 is able to bind LYVE-1 using AlphaScreen, or after surface-immobilization or in solution. FGF2 binds to LYVE-1 with a higher affinity than any other known LYVE-1-binding molecules, such as hyaluronan or PDGF-BB. Glycosylation of LYVE-1 is important for FGF2 binding. IntroductionThe lymphatic system is important to maintain fluid homeostasis by collecting fluid that leaks from capillary blood vessels and returning it to the blood circulation. 1 Perturbations in the development, maintenance and function of the lymphatic system can lead to a variety of pathologic lymphatic disorders including lymphedema, inflammation, and tumor metastasis. 2 The understanding of the molecular and cellular regulation of lymphangiogenesis has greatly advanced in recent years with the identification of the lymphangiogenic vascular endothelial growth factors VEGF-C and VEGF-D and their lymphatic vessel-specific VEGF receptor-3. 3 The repertoire of lymphangiogenic factors increased when it became apparent that other growth factor molecules or angiogenic factors were also regulating lymphangiogenesis. [4][5][6] As such, it has been recognized that FGF2 induces lymphangiogenesis by both direct and indirect mechanisms; it binds lymphatic endothelial cells (LECs) and stimulates their proliferation and migration in vitro 7,8 ; in addition, recent findings suggested that FGF2 reciprocally interacts with VEGF-C leading to additive lymphangiogenic activity and metastasis. 9,10 LYVE-1 (lymphatic vessel endothelial hyaluronan receptor-1), a homolog of hyaluronan receptor CD44, is expressed predominantly on lymphatic endothelium. 11 It is equally exposed to both the luminal and subluminal face of lymphatic vessel. 12 LYVE-1 cDNA encodes a 322-residue type-I integral membrane glycoprotein with a 21-residue transmembrane domain and a 63-residue cytoplasmic region. Similar to CD44, LYVE-1 has a single hyaluronan-binding domain at the N-terminus followed by a juxtamembrane region that is predicted to be heavily glycosylated. 12 LYVE-1 is also expressed in discrete populations of activated tissue macrophages and in the sinusoidal endothelium of the liver and the spleen, as well as in cancer tissues. 11,[13][14][15] LYVE-1 has been proposed to pa...

Mouse Proepicardium Exhibits a Sprouting Response to Exogenous Proangiogenic Growth Factors in vitro

“…Overexpression of VEGF-A 164 leads to the formation of giant lymphatic vessels in the mouse ear [37]. bFGF, on the other hand, can directly interact with the Lyve-1 receptor and, furthermore, upregulate the expression of Lyve-1 in cultured lymphatic ECs and in vivo in a corneal lymphangiogenesis assay [38]. In the PE, lymphangioblasts were not detected [39], consistent with our results.…”

Lymphangiogenic factors, mechanisms, and applications

“…These results indicate that FGF2 acts indirectly to promote lymphangiogenesis. Interestingly, LYVE1, a common lymphatic marker with elusive function, was recently found to bind FGF2 and to promote FGF2-induced signaling activation and lymphangiogenesis (67). Overall, such results could be explained if, for example, FGFR1 and VEGFR3 bind a common signal transducer in LECs.…”

Ectodomain Shedding of Lymphatic Vessel Endothelial Hyaluronan Receptor 1 (LYVE-1) Is Induced by Vascular Endothelial Growth Factor A (VEGF-A)

“…A recent study indicated that soluble LYVE-1 may interfere with migration and proliferation of LECs by binding directly to fibroblast growth factor-2 (FGF-2) in vitro and in vivo (24). FGF-2 and VEGF-C collaboratively promote tumor growth, angiogenesis, intratumoral lymphangiogenesis, and metastasis (25).…”