Cx47 fine-tunes the handling of serum lipids but is dispensable for lymphatic vascular function

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.

Regulatory role of oligodendrocyte gap junctions in inflammatory demyelination

“…Although we found no evidence for a direct involvement of Cx47 in the peripheral cellular immune response, Cx47 expression in lymphatic epithelium (Meens et al, 2017;Munger, Davis, & Simon, 2017) may suggest a possible role in peripheral immune reactions.…”

“…Although we found no evidence for a direct involvement of Cx47 in the peripheral cellular immune response, Cx47 expression in lymphatic epithelium (Meens et al, ; Munger, Davis, & Simon, ) may suggest a possible role in peripheral immune reactions. This could be relevant for the heightened CNS B cell response in Cx47KO EAE brains, since the pathway from brain lymphatics to draining cervical lymph nodes may modulate the CNS immune response (Louveau, Da Mesquita, & Kipnis, ).…”

Endothelial connexins in vascular function

“…Although mutations in the GJC2 gene predispose for human lymphedema, Cx47 expression is only sporadically detected in lymphatic ECs of the embryonic and adult mouse (22,62). Moreover, Cx47 deficiency did not affect lymphatic contractility or morphology nor interstitial fluid drainage in adult mice (62). It has recently been reported that human venous valve disease may be caused by mutations in the GJC2 gene.…”

“…Mice with a lymphatic EC-specific ablation of Cx43 show a delayed initiation, reduced frequency and incomplete maturation of lymphatic valves and altered lymphatic capillary patterning, resulting in leaky valves, insufficient lymphatic transport and a high incidence of lethal chylothorax, a milky effusion around the heart and lungs, in the first 6 months of life (61). Although mutations in the GJC2 gene predispose for human lymphedema, Cx47 expression is only sporadically detected in lymphatic ECs of the embryonic and adult mouse (22,62). Moreover, Cx47 deficiency did not affect lymphatic contractility or morphology nor interstitial fluid drainage in adult mice (62).…”

The role of oligodendrocyte gap junctions in neuroinflammation

“…Whether a direct involvement of Cx47 in the peripheral cellular immune response could contribute to the exacerbated EAE pathology in the CNS of Cx47 KO mouse remains to be clarified. Cx47 expression in the lymphatic epithelium [106,107] suggests a possible role in peripheral immune reactions. This could be one of the reasons for the heightened B-cell response in Cx47 KO EAE brains, since the pathway from brain lymphatics to draining Figure 1.…”