Lymphatic dysfunction in transgenic mice expressing KSHV k-cyclin under the control of the VEGFR-3 promoter.
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.
Sugaya
Makoto
M
Dermatology Branch, National Cancer Institute, Office of Research Services, Division of Veterinary Resources, Bethesda, MD, USA.
Watanabe
Takahiro
T
Yang
Aparche
A
Starost
Matthew F
MF
Kobayashi
Hisataka
H
Atkins
April M
AM
Borris
Debra L
DL
Hanan
Elisabeth A
EA
Schimel
Daniel
D
Bryant
Mark A
MA
Roberts
Nicole
N
Skobe
Mihaela
M
Staskus
Katherine A
KA
Kaldis
Philipp
P
Blauvelt
Andrew
A
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
D056741:Cyclin D; D016213:Cyclins; D014764:Viral Proteins; D040321:Vascular Endothelial Growth Factor Receptor-3