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A Novel Mouse Model of Inducible Lymphangiogenesis Through Controlled Local Expression of VEGF‐D
Author(s) -
Rutkowski Joseph M
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.726.7
Subject(s) - lymphangiogenesis , lymphatic system , cancer research , vascular endothelial growth factor c , lymphatic endothelium , cd146 , biology , vascular endothelial growth factor , pathology , microbiology and biotechnology , vascular endothelial growth factor a , medicine , cancer , metastasis , vegf receptors , stem cell , cd34
Lymphatic vessels are an integral part of the body's circulatory system. Lymphatic circulation modulates tissue fluid balance and inflammation and provides a conduit for endocrine and lipid transport as well as a pathway for cancer cell metastasis. The growth of new lymphatic vessels in the adult – lymphangiogenesis – is predominantly mediated through vascular endothelial growth factor receptor‐3 (VEGFR‐3) signaling upon binding of its ligands VEGF‐C and VEGF‐D. Lymphangiogenesis may be therapeutic in conditions of lymphatic deficiency (e.g., post‐lymphadenectomy), but may also be a negative driver of lymphatic proliferative pathologies such as GLA, Gorham‐Stout disease, and lymphangioleiomyomatosis. While human VEGF‐C and –D both can bind VEGFR‐2 as well, mouse VEGF‐D only binds VEGFR‐3. We took advantage of this unique interaction and generated mice capable of inducible, tissue‐specific expression of VEGF‐D under a tightly‐controlled tetracycline response element (TRE) promoter. This limits VEGF‐D expression to be cell‐specific and only upon doxycycline (administered in the water or chow) activation, thus providing a novel model of local lymphangiogenesis. We confirmed tight, dose‐responsive VEGF‐D expression with the TRE‐VEGF‐D mouse crossed to mice with tissue‐specific promoters for the lung (CCSP‐rtTA), kidney (KSP‐rtTA), and adipose tissue (adiponectin‐rtTA). Induction of VEGF‐D expression in these tissues resulted in marked lymphatic endothelial cell massive lymphatic vessel hyperplasia and hypertrophy. 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. Support or Funding Information AHA 12SDG12050287