title: Hyperplasia, de novo lymphangiogenesis, and lymphatic regression in mice with tissue-specific, inducible overexpression of murine VEGF-D.
abstract: Lymphatic vessels modulate tissue fluid balance and inflammation and provide a conduit for endocrine and lipid transport. The growth of new lymphatic vessels in the adult, lymphangiogenesis, is predominantly mediated through vascular endothelial growth factor receptor-3 (VEGFR-3) signaling. We took advantage of the unique binding of murine VEGF-D specifically to VEGFR-3 and generated mice capable of inducible, tissue-specific expression of murine VEGF-D under a tightly-controlled tetracycline response element (TRE) promoter to stimulate adult tissue lymphangiogenesis. With doxycycline-activated expression, TRE-VEGF-D mouse crossed to mice with tissue-specific promoters for the lung [Clara cell secretory protein-reverse tetracycline transactivator (rtTA)] developed pulmonary lymphangiectasia. In the kidney, (kidney-specific protein-rtTA × TRE-VEGF-D) mice exhibited rapid lymphatic hyperplasia on induction of VEGF-D expression. Crossed with adipocyte-specific adiponectin-rtTA mice [Adipo-VEGF-D (VD)], chronic VEGF-D overexpression was capable of inducing de novo lymphangiogenesis in white adipose tissue and a massive expansion of brown adipose tissue lymphatics. VEGF-D expression in white adipose tissue also increased macrophage infiltration and tissue fibrosis in the tissue. Expression did not, however, measurably affect peripheral fluid transport, the blood vasculature, or basal metabolic parameters. On removal of the doxycycline stimulus, VEGF-D expression returned to normal, and the expanded adipose tissue lymphatics regressed in Adipo-VD mice. The inducible TRE-VEGF-D mouse thus provides a novel murine platform to study the adult mechanisms and therapies of an array of disease- and tissue-specific models of lymphangiogenesis.
authors.affiliation: Division of Lymphatic Biology, Department of Medical Physiology, Texas A&M Health Science Center School of Medicine, College Station, Texas;
authors.forename: Gabriela M
authors.initials: GM
authors.lastname: Lammoglia
authors.affiliation: Division of Lymphatic Biology, Department of Medical Physiology, Texas A&M Health Science Center School of Medicine, College Station, Texas;
authors.forename: Carolynn E
authors.initials: CE
authors.lastname: Van Zandt
authors.affiliation: Division of Lymphatic Biology, Department of Medical Physiology, Texas A&M Health Science Center School of Medicine, College Station, Texas;
authors.forename: Daniel X
authors.initials: DX
authors.lastname: Galvan
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; and.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Orozco
authors.affiliation: Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Dellinger
authors.affiliation: Division of Lymphatic Biology, Department of Medical Physiology, Texas A&M Health Science Center School of Medicine, College Station, Texas; Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; and rutkowski@tamu.edu.
authors.forename: Joseph M
authors.identifier: 0000-0002-4197-0236
authors.initials: JM
authors.lastname: Rutkowski
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism* / Q000473:pathology; D052436:Adipose Tissue, White / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001823:Body Composition; D005260:Female; D005455:Fluorescent Antibody Technique; D006965:Hyperplasia; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008198:Lymph Nodes / Q000378:metabolism* / Q000473:pathology; D042583:Lymphangiogenesis / Q000235:genetics*; D042601:Lymphatic Vessels / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042643:Vascular Endothelial Growth Factor D / Q000235:genetics*; D040321:Vascular Endothelial Growth Factor Receptor-3
chemical_list: D042643:Vascular Endothelial Growth Factor D; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: VEGFR-3; adipose tissue; kidney; lymphangiectasia; lymphangiogenesis