Defective lymphatic valve development and chylothorax in mice with a lymphatic-specific deletion of Connexin43

Abstract

Lymphatic valves (LVs) are cusped luminal structures that permit the movement of lymph in only one direction and are therefore critical for proper lymphatic vessel function. Congenital valve aplasia or agenesis can, in some cases, be a direct cause of lymphatic disease. Knowledge about the molecular mechanisms operating during the development and maintenance of LVs may thus aid in the establishment of novel therapeutic approaches to treat lymphatic disorders. In this study, we examined the role of Connexin43 (Cx43), a gap junction protein expressed in lymphatic endothelial cells (LECs), during valve development. Mouse embryos with a null mutation in Cx43 (Gja1) were previously shown to completely lack mesenteric LVs at embryonic day 18. However, interpreting the phenotype of Cx43−/− mice was complicated by the fact that global deletion of Cx43 causes perinatal death due to heart defects during embryogenesis. We have now generated a mouse model (Cx43ΔLEC) with a lymphatic-specific ablation of Cx43 and show that the absence of Cx43 in LECs causes a delay (rather than a complete block) in LV initiation, an increase in immature valves with incomplete leaflet elongation, a reduction in the total number of valves, and altered lymphatic capillary patterning. The physiological consequences of these lymphatic changes were leaky valves, insufficient lymph transport and reflux, and a high incidence of lethal chylothorax. These results demonstrate that the expression of Cx43 is specifically required in LECs for normal development of LVs.

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, ).…”

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

“…More recently, Cx47 has also been detected in lymphatic valve LECs of young mice [10, 11, 13]. Here, we studied expression of Cx47 in lymphatics of adult mice.…”

Endothelial connexins in vascular function

“…Cx37 −/− mice show perturbed lymphatic valve formation resulting in virtual absence of valves and significant lymphedema in adults (22,23). 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).…”