Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3

Abstract

The lymphatic vasculature transports extravasated tissue fluid, macromolecules and cells back into the blood circulation. Recent reports have focused on the molecular mechanisms regulating the lymphatic vessels. Vascular endothelial growth factor (VEGF)-C and VEGF-D have been shown to stimulate lymphangiogenesis and their receptor, VEGFR-3, has been linked to human hereditary lymphedema. Here we show that a soluble form of VEGFR-3 is a potent inhibitor of VEGF-C/VEGF-D signaling, and when expressed in the skin of transgenic mice, it inhibits fetal lymphangiogenesis and induces a regression of already formed lymphatic vessels, though the blood vasculature remains normal. Transgenic mice develop a lymphedema-like phenotype characterized by swelling of feet, edema and dermal fibrosis. They survive the neonatal period in spite of a virtually complete lack of lymphatic vessels in several tissues, and later show regeneration of the lymphatic vasculature, indicating that induction of lymphatic regeneration may also be possible in humans.

Cotargeting of VEGFR-1 and -3 and angiopoietin receptor Tie2 reduces the growth of solid human ovarian cancer in mice

“…Adenoviral vectors encoding sVEGFR-1-IgG (immunoglobulin) fusion protein (AdsVEGFR-1), [27][28][29] sVEGFR-3-IgG fusion protein (AdsVEGFR-3), 30,31 soluble Tie1-IgG (AdsTie1), soluble Tie2-IgG (AdsTie2) 32, and LacZ (AdLacZ) as a control vector were used for the study. Replication-deficient E1-E3-deleted clinical good manufacturing practice (GMP)-grade adenoviruses were produced in 293T cells.…”

Vascular endothelial growth factors C and D and lymphangiogenesis in gastrointestinal tract malignancy

“…Transgenic mouse models, which overexpress VEGF-C or VEGF-D in the epidermis, have shown cytokine-dependent, VEGFR3-mediated dermal lymphatic vessel enlargement and lymphatic endothelial cell proliferation without alteration in blood vasculature Makinen et al, 2001;Veikkola et al, 2001). Various tumour models have been constructed in which overexpression of VEGF-C or VEGF-D is demonstrated.…”

Mesenchymal expression of vascular endothelial growth factors D and A defines vascular patterning in developing lung

“…The binding of VEGF-D or closely related VEGF-C to VEGFR-3 is required for development of the lymphatic vascular system (Mä kinen et al, 2001;Veikkola et al, 2001). In the lung, lymphatics play a critical role at and after birth, draining excessive fluid from the pulmonary interstitium and allowing efficient gas exchange.…”