TABLE 1.

Animal models of lymphedema.

	Species	Models	Pathophysiology observed	References
Surgical models	Mouse	Tail incision	Increase adipose deposition and adipocyte hypertrophy Macrophages surrounding subcutaneous fat deposits Collagen deposition within subcutaneous fat & collecting lymphatic vessels Changes in immune cell infiltrate Enlarged lymphatic capillaries Loss of function of both initial & collecting lymphatic vessels Increase in VEGF-C locally and systemically	Rutkowski et al., 2010; Zampell et al., 2012a; Cuzzone et al., 2014; Gousopoulos et al., 2016b, 2017; Jun et al., 2017
	Dog Mouse Rat Monkey Pig	Lymph node dissection/removal & radiation	Sustained tissue inflammation Decreased number of regeneration lymphatics Worsened swelling & lymph drainage Reduced fluid transport Dilated lymphatic vessels Increase volume in affected limb Lymph backflow	Knight et al., 1987; Blum et al., 2010; Lahteenvuo et al., 2011; Cuzzone et al., 2014; Wu et al., 2014; Yang et al., 2014; Triacca et al., 2019; Wang et al., 2020
	Mouse Rat	Hind limb incision	Swelling & impaired lymph drainage Insufficient wound healing Reduced lymph transport Dilated lymph vessels Increased fibrosis	Lynch et al., 2015; Jun et al., 2017; Jørgensen et al., 2018
	Rabbit	Ear incision	Dermal backflow Disrupted lymphatic flow Fibrosis Lymphatic vessels dilated and increased in number	Fu et al., 1998; Szuba et al., 2002; Yoon et al., 2003; Fernández Peñuela et al., 2018
Transgenic mouse models	Mouse	Chy Chy-3	Swelling in forepaw and hindpaw Higher levels of collagen and fat in skin Devoid of initial lymphatics in dermis Defective lymphatic vessels Decreased lymph flow	Karkkainen et al., 2001; Karlsen et al., 2006, 2012; Dellinger et al., 2007; Rutkowski et al., 2010
	Mouse	Prox1±	Baseline lymphatic dysfunction Impaired lymphatic transport & leaky lymphatics Impaired immune cell migration Increased inflammation after lymph node removal Defective lymphatic vasculature	Srinivasan et al., 2014; Hespe et al., 2019
	Mouse	K14-VEGFR-3-Ig (sR3)	Lack dermal lymphatics Smaller adipocytes Increased M2 macrophages Lack of podoplanin positive vessels in tail & back skin Regression of developing lymphatics	Mäkinen et al., 2001; Karaman et al., 2015
		FLT4-DTR	Mimic chronic lymphedema Initial swelling resolved temporarily, followed by late onset of lymphedema CD4 + infiltration Inhibition of lmyphagiogenesis Sclerosis of collecting lymphatic vessels	Gardenier et al., 2016