Dermal Collagen and Lipid Deposition Correlate with Tissue Swelling and Hydraulic Conductivity in Murine Primary Lymphedema

Abstract

Primary lymphedema is a congenital pathology of dysfunctional lymphatic drainage characterized by swelling of the limbs, thickening of the dermis, and fluid and lipid accumulation in the underlying tissue. Two mouse models of primary lymphedema, the Chy mouse and the K14-VEGFR-3-Ig mouse, both lack dermal lymphatic capillaries and exhibit a lymphedematous phenotype attributable to disrupted VEGFR-3 signaling. Here we show that the differences in edematous tissue composition between these two models correlated with drastic differences in hydraulic conductivity. The skin of Chy mice possessed significantly higher levels of collagen and fat, whereas K14-VEGFR-3-Ig mouse skin composition was relatively normal, as compared with their respective wild-type controls. Functionally, this resulted in a greatly increased dermal hydraulic conductivity in K14-VEGFR3-Ig, but not Chy, mice. Our data suggest that lymphedema associated with increased collagen and lipid accumulation counteracts an increased hydraulic conductivity associated with dermal swelling, which in turn further limits interstitial transport and swelling. Without lipid and collagen accumulation, hydraulic conductivity is increased and overall swelling is minimized. These opposing tissue responses to primary lymphedema imply that tissue remodeling--predominantly collagen and fat deposition--may dictate tissue swelling and govern interstitial transport in lymphedema.

Lymphatic vessels regulate immune microenvironments in human and murine melanoma

“…This was not a result of an impaired microenvironment within the lung itself, as intravenously administered tumor cells were able to effectively colonize lungs in both strains. In our case, LN metastasis may be a route of systemic dissemination, as tumor cells move through collecting lymphatic vessels remaining in subcutaneous tissue (37) and eventually re-enter circulation via the thoracic duct (17). While direct evidence for lymphatic vessel-mediated systemic spread is lacking and the efficacy of sentinel LN resection as a means of preventing metastatic spread is controversial (46,47), these data indicate that lymphatic vessels contribute to a more metastatic phenotype within primary tumor microenvironments.…”

“…Other architectural changes within skin present in the K14-VEGFR3-Ig mice may also influence immune infiltration in the tumor context or metastasis. Subcutaneous lipid deposition is not elevated in K14-VEGFR3-Ig mice, unlike the Chy mutant mice (37). Chy mice, but not K14-VEGFR3-Ig mice, exhibit increased dermal collagen content, and K14-VEGFR3-Ig mice demonstrate enhanced hydraulic conductivity as compared with WT littermates (37).…”

“…Subcutaneous lipid deposition is not elevated in K14-VEGFR3-Ig mice, unlike the Chy mutant mice (37). Chy mice, but not K14-VEGFR3-Ig mice, exhibit increased dermal collagen content, and K14-VEGFR3-Ig mice demonstrate enhanced hydraulic conductivity as compared with WT littermates (37). Consistent with this, no difference between collagen content or α-SMA was detected in skin of transgenic mice, either at steady state or in association with an implanted tumor.…”

“…Given the We confirmed this phenotype in a second model of lymphatic vessel dysfunction (Chy mice, C3H background). Chy mice harbor a heterozygous inactivating mutation in the tyrosine kinase domain of VEGFR3 (36), causing a decrease in lymphatic transport from skin (37). Notably, in this model, dermal lymphatic vessels have been shown to be mostly absent in extremities (i.e., forelimb and ear skin), while trunk skin contains sparse residual lymphatic capillaries able to support cellular egress from tissue (6).…”

Increased Hyaluronan Expression at Distinct Time Points in Acute Lymphedema

“…Collagen and lipid deposition, for example, have been shown to increase in swollen skin. 1,2 In addition to collagens, which strengthen the tensile properties of skin to counteract the swelling force, glycosaminoglycans (GAGs) increase tissue hydrostatic pressure by stabilizing water (ie, restricting water mobility) due to their high negative charge density.…”