## 4 Discussion
### LyV Remodeling Is Part of Cardiac Remodeling  
Several processes are associated with the structural remodeling of LyVs: rarefaction of lymphatic capillaries and changes in their wall shape and wall structure. In our studies, the shape of the vessels was clearly different in the db/db and in Ang II-treated db/db mice (vs. the control), presumably depending on the altered myocardium, including the interstitial tissue, due to specific environmental conditions. We observed folding of the LyV walls in the control mice treated with Ang II, which also exhibited increased myocardial fibrosis, variable irregular shapes in the db/db mice with a moderate increase in the collagen amount in the interstitial area, and oval shapes in the tissue with intensive collagen deposition adjacent to LyVs in the Ang II-treated db/db mice. These differences in the LyV shape may relate to the different activities of MMPs and collagen composition, as indicated by the results of other researchers, including differences in the mRNA expression for matrix metalloproteinase 2 (MMP2), Coll I and Coll III [52]. The proximity of collagen deposits may be the reason for the preserved oval shape of the initials. This may make these vessels resistant to elevated interstitial fluid pressure. Similar observations have been reported in reference to lymphatic vessels in the hearts of hypertensive Dahl S rats [38]. The main structural anomalies in the LyVs were expressed by abnormal organization of AnchFs into bundles and almost a complete absence of AnchFs in the Ang II-treated db/db mice; the marked expression of structural features related to impaired transport of fluids, molecules, and cells through the wall, i.e., widened gaps at intercellular junctions, in the obese and Ang II-treated mice; and a significant decrease in the number of cytoplasmic vesicles in both groups of obese mice. The functional significance of AnchFs for primary valve function is still discussed [99; 100]. It has been hypothesized that high interstitial fluid pressure acts on AnchFs and thus opens pull-up flaps without the need for LEC junction dissolution to facilitate the transport of fluid, solutes, and cells via the paracellular route [26; 27; 28; 99; 101; 102]. However, there are also other suggestions for the role of AnchFs, i.e., maintenance of the LyV shape or the transduction of signals from local forces [100]. Previous observations by [PERSON] and [PERSON] [35; 103] demonstrated a relationship between the absence of anchoring filament protein Emilin-1 and dysfunctional LyVs, as well as an improvement of LyV function after restoring anchoring filament protein expression. Another protein that constitutes AnchFs is fibrillin, which is involved in mechanotransduction and sensing of lymph pulsatile movement, and its presence is crucial for normal LyV function [104; 105]. Therefore, the alterations in or disappearance of AnchFs may reflect the impaired absorbing function of LyVs, as reported by others in transgenic animal models, in cancer, and in inflammation [27; 106; 107; 108; 109]. Moreover, the observed alterations in the AnchFs in our study are accompanied by anomalies in the LEC flaps in both the Ang II-treated controls and Ang II-treated db/db mice. A normal ECM generates passive tension, which protects against excessive myocardial stretching as well as allows the opening of the LEC flaps for fluid and solute drainage from the ECM during increased interstitial pressure due to fluid accumulating in the extracellular space [110]. In contrast, a stiff ECM impairs force transmission during cardiac systole and diastole [111] and affects the actin filament alignment in the LECs, leading to rupture of their anchoring points [112; 113]. We do not know whether such a process occurs in mice treated with Ang II. In fact, the dense masses of collagen located in the vicinity of the flaps in the Ang II-treated db/db mice certainly induced stiffness in this area and impeded the movement of the flaps, already limited by the AnchF alterations.