Mechanisms of Connexin-Related Lymphedema

• DOI: 10.1161/circresaha.117.312576
• Publication Date: 2018-09-29T05:27:28Z
• Authors: Jorge A. Castoren...; Scott D. Zawieja; Min Li; R. Sathish Sriniv...; Alexander M. Simon; Cor de Wit; Roger de la Torre; Luis A. Martinez-...; Grant W. Hennig; Michael J. Davis
• Keywords: Lymphatic Endothelium; Ex vivo

Rationale: Mutations in GJC2 and GJA1 , encoding Cxs (connexins) 47 43, respectively, are linked to lymphedema, but the underlying mechanisms unknown. Because efficient lymph transport relies on coordinated contractions of lymphatic muscle cells (LMCs) their electrical coupling through Cxs, Cx-related lymphedema is proposed result from dyssynchronous vessels. Objective: To determine which Cx isoforms LMCs endothelial required for entrainment contraction waves transport. Methods Results: We developed novel methods quantify spatiotemporal used optogenetic techniques analyze calcium signaling within between LMC cell layers. Genetic deletion major (Cx43, Cx47, or Cx37) revealed that none were necessary synchronization global events triggered propagating waves. identified Cx45 human mouse as critical mediating conduction pacemaking signals entrained contractions. Smooth muscle–specific deficiency resulted 10- 18-fold reduction speed, partial-to-severe loss contractile coordination, impaired pump function ex vivo vivo. profound inhibition vivo, only under an imposed gravitational load. Conclusions: Our results (1) identify isoform LMCs; (2) show dispensable contractions; (3) reveal a lack LMCs, contrast arterioles; (4) point valve defects, rather than dyssynchrony, mechanism - -related lymphedema; (5) load exacerbates defects intact hindlimb, likely development adult mouse.