Therapeutic lymphangiogenesis with human recombinant VEGF-C.
Chronic regional impairments of the lymphatic circulation often lead to striking architectural abnormalities in the lymphedematous tissues. Lymphedema is a common, disabling disease that currently lacks a cure. Vascular endothelial growth factors C and D mediate lymphangiogenesis through the VEGFR-3 receptor on lymphatic endothelia. The purpose of this study was to investigate the therapeutic potential for lymphangiogenesis with VEGF-C. We developed a rabbit ear model to simulate human chronic postsurgical lymphatic insufficiency. Successful, sustained surgical ablation of the ear lymphatics was confirmed by water displacement volumetry. After complete healing, the experimental animals (n=8) received a single, s.c. 100 microg dose of VEGF-C in the operated ear; controls (n=8) received normal saline. Radionuclide lymphoscintigraphy was performed to quantitate lymphatic function. Immunohistochemistry (IHC) was performed 7-8 days following treatment. After VEGF-C, there was a quantifiable amelioration of lymphatic function. IHC confirmed a significant increase in lymphatic vascularity, along with reversal of the intense tissue hypercellularity of untreated lymphedema. This study confirms the capacity of a single dose of VEGF-C to induce therapeutic lymphangiogenesis in acquired lymphedema. In addition to improving lymphatic function and vascularity, VEGF-C can apparently reverse the abnormalities in tissue architecture that accompany chronic lymphatic insufficiency.
Szuba
Andrzej
A
Division of Cardiovascular Medicine, Falk Cardiovascular Research Center, Stanford University School of Medicine, Stanford, California 94305, USA.
Skobe
Mihaela
M
Karkkainen
Marika J
MJ
Shin
William S
WS
Beynet
David P
DP
Rockson
Ned B
NB
Dakhil
Noma
N
Spilman
Stan
S
Goris
Michael L
ML
Strauss
H William
HW
Quertermous
Thomas
T
Alitalo
Kari
K
Rockson
Stanley G
SG
D000818:Animals; D002908:Chronic Disease; D020405:Dermis / Q000473:pathology; D016228:Endothelial Growth Factors / Q000235:genetics / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D008208:Lymphatic System / Q000187:drug effects* / Q000254:growth & development / Q000503:physiopathology; D008209:Lymphedema / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D011817:Rabbits; D011994:Recombinant Proteins / Q000627:therapeutic use; D012867:Skin / Q000473:pathology; D042582:Vascular Endothelial Growth Factor C
D016228:Endothelial Growth Factors; D011994:Recombinant Proteins; D042582:Vascular Endothelial Growth Factor C