Decline of lymphatic vessel density and function in murine skin during aging
- 754 Downloads
Lymphatic vessels play important roles in the pathogenesis of many conditions that have an increased prevalence in the elderly population. However, the effects of the aging process on the lymphatic system are still relatively unknown. We have applied non-invasive imaging and whole-mount staining techniques to assess the lymphatic vessel function and morphology in three different age groups of mice: 2 months (young), 7 months (middle-aged), and 18 months (aged). We first developed and validated a new method to quantify lymphatic clearance from mouse ear skin, using a lymphatic-specific near-infrared tracer. Using this method, we found that there is a prominent decrease in lymphatic vessel function during aging since the lymphatic clearance was significantly delayed in aged mice. This loss of function correlated with a decreased lymphatic vessel density and a reduced lymphatic network complexity in the skin of aged mice as compared to younger controls. The blood vascular leakage in the skin was slightly increased in the aged mice, indicating that the decreased lymphatic function was not caused by a reduced capillary filtration in aged skin. The decreased function of lymphatic vessels with aging might have implications for the pathogenesis of a number of aging-related diseases.
KeywordsAging Lymphatic vessels Vascular leakage In vivo imaging
The authors thank Jeannette Scholl and Carlos Ochoa for excellent technical assistance. This work was supported by Swiss National Science Foundation Grants 3100A0-108207 and 31003A-130627, Advanced European Research Council Grant LYVICAM, Oncosuisse, Krebsliga Zurich, and Leducq Transatlantic Network of Excellence on Lymph Vessels in Obesity and Cardiovascular Disease (11CVD03).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
- 3.Martel C, Li W, Fulp B, Platt AM, Gautier EL, Westerterp M, Bittman R, Tall AR, Chen SH, Thomas MJ, Kreisel D, Swartz MA, Sorci-Thomas MG, Randolph GJ (2013) Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice. J Clin Invest 123(4):1571–1579. doi: 10.1172/JCI63685 PubMedCentralCrossRefPubMedGoogle Scholar
- 4.Lim HY, Thiam CH, Yeo KP, Bisoendial R, Hii CS, McGrath KCY, Tan KW, Heather A, Alexander JSJ, Angeli V (2013) Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-mediated transport of HDL. Cell Metab 17(5):671–684. doi: 10.1016/j.cmet.2013.04.002 CrossRefPubMedGoogle Scholar
- 5.Wiig H, Schroder A, Neuhofer W, Jantsch J, Kopp C, Karlsen TV, Boschmann M, Goss J, Bry M, Rakova N, Dahlmann A, Brenner S, Tenstad O, Nurmi H, Mervaala E, Wagner H, Beck FX, Muller DN, Kerjaschki D, Luft FC, Harrison DG, Alitalo K, Titze J (2013) Immune cells control skin lymphatic electrolyte homeostasis and blood pressure. J Clin Invest 123(7):2803–2815. doi: 10.1172/JCI60113 PubMedCentralCrossRefPubMedGoogle Scholar
- 15.Proulx ST, Luciani P, Christiansen A, Karaman S, Blum KS, Rinderknecht M, Leroux JC, Detmar M (2013) Use of a PEG-conjugated bright near-infrared dye for functional imaging of rerouting of tumor lymphatic drainage after sentinel lymph node metastasis. Biomaterials 34(21):5128–5137. doi: 10.1016/j.biomaterials.2013.03.034 PubMedCentralCrossRefPubMedGoogle Scholar
- 21.Karaman S, Hollmen M, Robciuc MR, Alitalo A, Nurmi H, Morf B, Buschle D, Alkan HF, Ochsenbein AM, Alitalo K, Wolfrum C, Detmar M (2015) Blockade of VEGF-C and VEGF-D modulates adipose tissue inflammation and improves metabolic parameters under high-fat diet. Mol Metab 4(2):93–105. doi: 10.1016/j.molmet.2014.11.006 PubMedCentralCrossRefPubMedGoogle Scholar
- 23.Lohela M, Heloterä H, Haiko P, Dumont DJ, Alitalo K (2008) Transgenic induction of vascular endothelial growth factor-C is strongly angiogenic in mouse embryos but leads to persistent lymphatic hyperplasia in adult tissues. Am J Pathol 173(6):1891–1901. doi: 10.2353/ajpath.2008.080378 PubMedCentralCrossRefPubMedGoogle Scholar
- 25.Markhus CE, Karlsen TV, Wagner M, Svendsen OS, Tenstad O, Alitalo K, Wiig H (2013) Increased interstitial protein because of impaired lymph drainage does not induce fibrosis and inflammation in lymphedema. Arterioscler Thromb Vasc Biol 33(2):266–274. doi: 10.1161/ATVBAHA.112.300384 CrossRefPubMedGoogle Scholar
- 27.Yabluchanskiy A, Ma Y, Chiao YA, Lopez EF, Voorhees AP, Toba H, Hall ME, Han HC, Lindsey ML, Jin YF (2014) Cardiac aging is initiated by matrix metalloproteinase-9-mediated endothelial dysfunction. Am J Physiol Heart Circ Physiol 306(10):H1398–H1407. doi: 10.1152/ajpheart.00090.2014 PubMedCentralCrossRefPubMedGoogle Scholar