title: Lymphatic dysfunction in transgenic mice expressing KSHV k-cyclin under the control of the VEGFR-3 promoter.
abstract: Kaposi sarcoma-associated herpesvirus (KSHV) infects endothelial cells within KS tumors, and these cells express the KSHV latent-cycle gene k-cyclin (kCYC) as well as vascular endothelial growth factor receptor 3 (VEGFR-3), a marker for lymphatic endothelium. To further understand KSHV-mediated pathogenesis, we generated transgenic mice expressing kCYC under the control of the VEGFR-3 promoter. kCYC mRNA and functional protein expression within tissue correlated with VEGFR-3 expression and were most abundantly detected within lung tissue. Clinically, most transgenic mice died within 6 months of age secondary to progressive accumulation of chylous pleural fluid. In skin, edema was detected by magnetic resonance imaging and mice demonstrated persistent erythema of the ears following trauma. Histologically, erythematous skin showed extravasation of erythrocytes and accumulation of erythrocytes within lymphatic lumens. In addition, lymphatic drainage of injected contrast dyes was markedly impaired in transgenic mice. Karyomegaly, a feature observed in kCYC-expressing cells in vitro, was detected in many tissues, and selectively occurred within lymphatic endothelial cells expressing kCYC mRNA by in situ hybridization. In summary, kCYC expression within VEGFR-3+ cells of mice causes marked impairment of lymphatic function. kCYC may contribute to the development of certain clinical and histologic features of KS, including localized edema and retention of extravasated erythrocytes within KS tumors.
authors.affiliation: Dermatology Branch, National Cancer Institute, Office of Research Services, Division of Veterinary Resources, Bethesda, MD, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sugaya
authors.forename: Takahiro
authors.initials: T
authors.lastname: Watanabe
authors.forename: Aparche
authors.initials: A
authors.lastname: Yang
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Starost
authors.forename: Hisataka
authors.initials: H
authors.lastname: Kobayashi
authors.forename: April M
authors.initials: AM
authors.lastname: Atkins
authors.forename: Debra L
authors.initials: DL
authors.lastname: Borris
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Hanan
authors.forename: Daniel
authors.initials: D
authors.lastname: Schimel
authors.forename: Mark A
authors.initials: MA
authors.lastname: Bryant
authors.forename: Nicole
authors.initials: N
authors.lastname: Roberts
authors.forename: Mihaela
authors.initials: M
authors.lastname: Skobe
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Staskus
authors.forename: Philipp
authors.initials: P
authors.lastname: Kaldis
authors.forename: Andrew
authors.initials: A
authors.lastname: Blauvelt
mesh_terms: D000818:Animals; D002467:Cell Nucleus; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D004487:Edema / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004729:Endothelium, Lymphatic / Q000378:metabolism / Q000473:pathology; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology; D019288:Herpesvirus 8, Human / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008206:Lymphatic Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012514:Sarcoma, Kaposi / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012868:Skin Abnormalities / Q000235:genetics / Q000473:pathology; D019076:Transgenes / Q000235:genetics; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics*; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D056741:Cyclin D; D016213:Cyclins; D014764:Viral Proteins; D040321:Vascular Endothelial Growth Factor Receptor-3