TY - JOUR
T1 - Secondary lymphedema in the mouse tail
T2 - Lymphatic hyperplasia, VEGF-C upregulation, and the protective role of MMP-9
AU - Rutkowski, Joseph M.
AU - Moya, Monica
AU - Johannes, Jimmy
AU - Goldman, Jeremy
AU - Swartz, Melody A.
N1 - Funding Information:
The authors are grateful to Dr. Hugo Schmoekel and Veronique Garea for invaluable assistance with the animals, Miriella Pasquier for sectioning, and Sai T. Reddy and Gabriela Miyazawa for helpful assistance. The authors thank the NIH (RO1-HL075217-01), NSF (BES-0134551), and The Swiss National Science Foundation for funding.
PY - 2006/11
Y1 - 2006/11
N2 - Disturbances in the microcirculation can lead to secondary lymphedema, a common pathological condition that, despite its frequency, still lacks a cure. Lymphedema is clinically well described, but while the genetic underpinnings that cause lymphatic malformations and primary lymphedema are being discovered, the pathophysiology and pathobiology of secondary lymphedema remain poorly understood, partly due to the lack of well-described experimental models. Here, we provide a detailed characterization of secondary lymphedema in the mouse tail and correlate the evolution of tissue swelling to changes in tissue architecture, infiltration of immune cells, deposition of lipids, and proliferation and morphology of the lymphatic vessels. We show that sustained swelling leads to lymphatic hyperplasia and upregulation of vascular endothelial growth factor (VEGF)-C, which may exacerbate the edema because the hyperplastic vessels are poorly functional. The onset of lymphatic hyperplasia occurred prior to the onset of lipid accumulation and peak VEGF-C expression. Langerhans dendritic cells were seen in the dermis migrating from the epidermis to the lymphatic capillaries in edematous tissue. Furthermore, these results were consistent between two different normal mouse strains, but swelling was significantly greater in a matrix metalloproteinase (MMP)-9 null strain. Thus, by characterizing this highly reproducible model of secondary lymphedema, we conclude that VEGF-C upregulation and lymphatic hyperplasia resulting from dermal lymphatic ligation and lymphedema leads to decreased drainage function and that MMP-9 may be important in counteracting tissue swelling.
AB - Disturbances in the microcirculation can lead to secondary lymphedema, a common pathological condition that, despite its frequency, still lacks a cure. Lymphedema is clinically well described, but while the genetic underpinnings that cause lymphatic malformations and primary lymphedema are being discovered, the pathophysiology and pathobiology of secondary lymphedema remain poorly understood, partly due to the lack of well-described experimental models. Here, we provide a detailed characterization of secondary lymphedema in the mouse tail and correlate the evolution of tissue swelling to changes in tissue architecture, infiltration of immune cells, deposition of lipids, and proliferation and morphology of the lymphatic vessels. We show that sustained swelling leads to lymphatic hyperplasia and upregulation of vascular endothelial growth factor (VEGF)-C, which may exacerbate the edema because the hyperplastic vessels are poorly functional. The onset of lymphatic hyperplasia occurred prior to the onset of lipid accumulation and peak VEGF-C expression. Langerhans dendritic cells were seen in the dermis migrating from the epidermis to the lymphatic capillaries in edematous tissue. Furthermore, these results were consistent between two different normal mouse strains, but swelling was significantly greater in a matrix metalloproteinase (MMP)-9 null strain. Thus, by characterizing this highly reproducible model of secondary lymphedema, we conclude that VEGF-C upregulation and lymphatic hyperplasia resulting from dermal lymphatic ligation and lymphedema leads to decreased drainage function and that MMP-9 may be important in counteracting tissue swelling.
KW - Extracellular matrix
KW - Lipid deposition
KW - Lymphatic function
KW - MMP-9
KW - VEGF-C
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U2 - 10.1016/j.mvr.2006.05.009
DO - 10.1016/j.mvr.2006.05.009
M3 - Article
C2 - 16876204
AN - SCOPUS:33750612559
SN - 0026-2862
VL - 72
SP - 161
EP - 171
JO - Microvascular Research
JF - Microvascular Research
IS - 3
ER -