Above, I have focused on describing the relationship between the hallmark functions of LS and AT. In this chapter, I discuss in more depth the functional interaction between AT and LS in pathologies associated with adipose (obesity) and lymphatic (lymphedema) diseases [238, 239].
3.3.1 Obesity
How does obesity regulate lymphatic function? Only a few years ago, research observations emerged to indicate that obesity can cause pathological changes in the lymphatic vasculature [126, 238, 240]. Moreover, obesity-related AT expansion and metabolic disturbances are
47 associated with defects in LV contractility and density [138, 241-243]. Obese mice exhibit impaired lymphatic function (leakage), decreased density of collecting LVs together with changes mRNA level of lymphatic markers with increased SAT deposition together with increased inflammation of CD45 + and CD4 + cells [244, 245]. Investigation of SAT lymphatic drainage in obese men has shown a reduced ability to remove macromolecules from the interstitial space through LS [138]. In a recent study, the high-fat diet significantly altered lymph transport, and both macro and microscopic anatomy of LNs in the mouse model [241]. Furthermore, the high-fat diet also showed an association with impaired LV collection function [246]. On the other hand, Karaman et al. [247] observed up-regulation of VEGF-C in SAT of obese mice. Since lymphatic drainage is reduced in obesity, it can be speculated that higher levels of VEGF-C are not sufficient to promote productive lymphangiogenesis and normalize drainage. We can envision that obesity limits local activation of pro-VEGF-C or, on the contrary, that upregulation of VEGF-C by obesity leads to excessive, but at the same time unproductive lymphangiogenesis, as seen in lymphedema.
Additionally, research data suggested a positive relationship between obesity and the development of breast cancer associated secondary lymphedema [248]. Therefore, being obese is a risk factor for the development of secondary lymphedema.
Fortunately, obesity-induced lymphatic dysfunction is reversible with lifestyle interventions.
Recent studies have shown that specific set up of aerobic exercise training markedly improved lymphatic function in obese sedentary mice model, despite having no effect on weight [249]. Importantly, exercise normalized levels of lymphatic markers (VEGFR-3 and PROX-1) [249]. In addition, another study analyzed the effect of weight loss on LV's function in mouse models. Briefly, switching from a high-fat diet to a chow diet for 8 weeks resulted in more than a 25% decrease in body weight, but more importantly, the rate of LV's pumping normalized, along with lymphatic leakage and their density [250]. Taken together, these findings have shown that simple obesity combined with sedentary behavior does not have a permanent effect on lymphatic dysfunction.
3.3.2 Lymphedema
Lymphedema is a chronic disorder that devastates tissues with all its humoral and cellular components [251]. It could be based on genetic insufficiency of LS, i.e. primary lymphedema is associated with genetic mutations of genes involved in the proper function
48 of LS. These are for example: FOXC-2 gene causing Lymphedema-distichiasis and VEGFR- 3 causing Milroy disease [140]. Secondary lymphedema is the most frequent sort of lymphedema in the world. Disease is caused by trauma, postnatal damage of LS induced by surgical and radiation therapy, or environmental factors (infection by worms from the genus Filariidae). Filarial lymphedema is caused by Filaria bancroffti, Brugia malayi, Brugia timori with the same edematous clinical signs [252].
Secondary upper extremity lymphedema is common in cancer patients and can be considered as iatrogenic damage via irradiation, chemotherapy and lymph node dissection or sentinel lymph node biopsy [140, 253]. Disease is characteristic with an accumulation of excess lymphatic fluid, retrograde lymphatic flow, hyperplasia of LVs connected with high fibrotic and mainly inflammatory changes [214, 254] regarded as critical component in the pathophysiology of lymphedema [254]. Last, but not least, enormous accumulation of SAT in upper and lower extremities is characterized in later stages of lymphedema [214, 254].
Despite substantial arrangements in surgical strategies and modern molecular and genetic therapy options, complete recovery from secondary lymphedema is still unattainable [255].
Conservative treatment is the most commonly used treatment for lymphedema and consists of non-instrumental and instrumental treatment. The physical, non-instrumental treatment includes complex decongestive therapy. This type of treatment must be applied life-long and significantly impairs quality of life. Instrumental treatment could include a liposuction procedure to reduce accumulated fat [140]. If non-surgical treatment fails or has inadequate results, therapies involving microsurgical interventions, i.e. transplantation of vascularised lymph nodes and lymphovenous bypass to provide partial restoration of the damaged lymphatic channels and drainage system, are emerging. Beederman et al. [253] have proven that the functional status of the affected limb is improved in patients who underwent microsurgical interventions.
Causality between defects of LS and accumulation of AT was described on mouse models of primary and secondary lymphedema. [212, 256]. In humans, Szolnoky et al. [257], Tashiro et al. [185] and Zhang et al. [258] have described hypertrophic pattern of AT in secondary lymphedema. However, a more detailed investigation of the qualities of lymphedema AT is still missing. Therefore a part of my thesis had provided comprehensive analysis of lymphedema AT qualities compared to healthy paired limbs and healthy subjects.
As described above extensive fat deposition in secondary lymphedema is associated with long-term lymphatic stasis and leakage of lymph that leads not only to hypertrophy but also
49 to hyperplasia of adipocytes [259]. Therefore, the investigators hypothesized that lymph/ISF could contain pro-adipogenic stimuli [212, 260] which is described in the next chapter.