Abstract
Mutations in the gap junction protein connexin47 (Cx47) are associated with lymphedema. However, the role of Cx47 in lymphatic pathophysiology is unknown. We demonstrate that Cx47 is expressed in lymphatic endothelial cells by whole-mount immunostaining and qPCR. To determine if Cx47 plays a role in lymphatic vessel function we analysed Cx47-/- mice. Cx47-deficiency did not affect lymphatic contractility (contractile amplitude or frequency) or lymphatic morphology (vessel diameter or number of valves). Interstitial fluid drainage or dendritic cell migration through lymphatic vessels was also not affected by Cx47-deficiency. Cx47 is dispensable for long-chain fatty acid absorption from the gut but rather promotes serum lipid handling as prolonged elevated triglyceride levels were observed in Cx47-deficient mice after oral lipid tolerance tests. When crossed with Apolipoprotein E-deficient (Apoe-/-) mice, LDL-cholesterol was decreased in young Cx47-/-Apoe-/- adults as compared to Apoe-/- mice, which was inverted later in life. Finally, advanced atherosclerotic plaques in thoracic-abdominal aortas of 15 months-old mice tended to be larger in Cx47-/-Apoe-/- mice. These plaques contained fewer macrophages but similar amounts of T lymphocytes, collagen and lipids than plaques of Apoe-/- mice. In conclusion, Cx47 is expressed in lymphatic endothelium and seems modestly implicated in multiple aspects of lymphatic pathophysiology.
Highlights
The incidence of lymphedema is still on the rise, proper treatment for this painful and crippling condition is unavailable
Cx47 expression was thought to be restricted to oligodendrocytes in the central nervous system (CNS), where they contribute to myelination [14,15,16]
Cx47 has been detected in lymphatic valve lymphatic endothelial cells (LECs) of young mice [10, 11, 13]
Summary
The incidence of lymphedema is still on the rise, proper treatment for this painful and crippling condition is unavailable. Connexins are transmembrane proteins that are expressed throughout the body. These proteins are inserted in cell membranes as hexamers (connexons) that can be composed of one or several types of connexins. Connexons can function as hemi-channels allowing for diffusion of small soluble factors from the cytosol to the extracellular space or vice versa. A connexon docks to a connexon expressed by an adjacent cell thereby forming a gap junction channel allowing for cytoplasmic exchange of ions and small metabolites between neighboring cells [6]. Gap junction channels are critically involved in direct cell-cell communication and synchronization of tissue responses [7, 8]
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