VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment

Abstract

Lymphangiogenesis, an important initial step in tumor metastasis and transplant sensitization, is mediated by the action of VEGF-C and -D on VEGFR3. In contrast, VEGF-A binds VEGFR1 and VEGFR2 and is an essential hemangiogenic factor. We re-evaluated the potential role of VEGF-A in lymphangiogenesis using a novel model in which both lymphangiogenesis and hemangiogenesis are induced in the normally avascular cornea. Administration of VEGF Trap, a receptor-based fusion protein that binds and neutralizes VEGF-A but not VEGF-C or -D, completely inhibited both hemangiogenesis and the outgrowth of LYVE-1+ lymphatic vessels following injury. Furthermore, both lymphangiogenesis and hemangiogenesis were significantly reduced in mice transgenic for VEGF-A164/164 or VEGF-A188/188 (each of which expresses only one of the three principle VEGF-A isoforms). Because VEGF-A is chemotactic for macrophages and we demonstrate here that macrophages in inflamed corneas release lymphangiogenic VEGF-C/VEGF-D, we evaluated the possibility that macrophage recruitment plays a role in VEGF-A–mediated lymphangiogenesis. Either systemic depletion of all bone marrow–derived cells (by irradiation) or local depletion of macrophages in the cornea (using clodronate liposomes) prior to injury significantly inhibited both hemangiogenesis and lymphangiogenesis. We conclude that VEGF-A recruitment of monocytes/macrophages plays a crucial role in inducing inflammatory neovascularization by supplying/amplifying signals essential for pathological hemangiogenesis and lymphangiogenesis

Low level arsenic promotes progressive inflammatory angiogenesis and liver blood vessel remodeling in mice

“…1 extend these earlier observations by demonstrating that angiogenesis enhanced by 5 wk arsenic exposures is associated with recruitment of inflammatory cells. This is in keeping with the pathogenesis of angiogenesis in adult tissues (Carmeliet, 2000;Cursiefen et al, 2004;Tsuneyama et al, 2003). However, these data were not unexpected, since the Matrigel plug is an inflammatory model primed with a threshold amount of FGF (Soucy et al, 2005).…”

“…Thus, as the fenestrations close the cells increase intracellular contacts and transport through the fenestrations is limited by gain of a basement membrane. Infiltration of leukocytes, especially pro-angiogenic myeloid cells, is necessary for supporting pathological angiogenesis, vessel maturation, and remodeling (Brasier et al, 2002;Carmeliet, 2000;Cursiefen et al, 2004;Ruiz et al, 2006). It is possible that the delayed increase in CD45 positive cell infiltration was the result of vessel maturation in the capillarization process rather than a direct effect of arsenic on leukocyte activity.…”

Interaction of tumor cells and lymphatic vessels in cancer progression

“…47,50 VEGF-A may also induce inflammation, including leukocyte recruitment that contributes to lymphangiogenesis. 51,52 Further complexity is added to the interactions of VEGF-C and VEGF-D with putative receptors by processing proteases and coreceptor binding ( Figure 1). Proteolytic cleavage of the VEGF-C and VEGF-D at their N and C termini modulates the affinities of the factors to VEGFR-2 and VEGFR-3, as well as to neuropilin (NRP) coreceptors.…”

Chemokines in cancer related inflammation

“…CXCL12 promotes tumor angiogenesis also by the local recruiting of circulating or bone marrow-derived endothelial precursors [65]. Both CXCR4 and CXCL12 are targets of the hypoxia transcription factor HIF-1α; during tumor-induced hypoxia both molecules are up-regulated in tumor cells, TAM and vessels and participate in the building of vascular network that is essential for tumor progression [18,66].…”