Secondary lymphedema in the mouse tail: Lymphatic hyperplasia, VEGF-C upregulation, and the protective role of MMP-9.
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.
Rutkowski
Joseph M
JM
Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Moya
Monica
M
Johannes
Jimmy
J
Goldman
Jeremy
J
Swartz
Melody A
MA
D000818:Animals; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology; D020405:Dermis / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D006965:Hyperplasia; D050356:Lipid Metabolism; D042601:Lymphatic Vessels / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D008209:Lymphedema / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008220:Lymphography; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D040521:Subcutaneous Tissue / Q000378:metabolism / Q000473:pathology; D013623:Tail / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D013997:Time Factors; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*
D042582:Vascular Endothelial Growth Factor C; C467483:vascular endothelial growth factor C, mouse; D003094:Collagen; D020780:Matrix Metalloproteinase 9