Institutt for biomedisin

BBB seminar: Michael John Davis

The conduction and coordination of propulsive lymphatic contractions


Michael John Davis
Department of Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, USA    

Mutations in gap junction proteins, connexins 47 and 43, are linked directly to both primary and secondary human lymphedema, but the reasons why are unknown. Because efficient lymph transport relies on the coordinated contractions of lymphatic smooth muscle cells (LMCs) and the electrical coupling of those cells through connexins (Cx), Cx-related lymphedema has been proposed to result from dyssynchronous contractions of collecting lymphatic vessels. To determine which connexin isoforms in lymphatic endothelium and/or smooth muscle are required for the conduction and entrainment of lymphatic contraction waves we developed novel methods to quantify the spatiotemporal entrainment of those waves in lymphatic vessels from normal and connexin-deficient mice. We also used optogenetic techniques to analyze calcium signaling within and between the LMC and lymphatic endothelial cell (LEC) layers. Membrane potential and calcium measurements in LECs and LMCs reveal that the two layers are not coupled and none of the major LEC connexins, Cx43, Cx47 or Cx37, are required for entrained contraction waves, or for synchronization of the calcium events that trigger those waves. However, genetic deletion of another connexin, Cx45, in the smooth muscle but not the endothelial layer, results in 10-20 fold reduction in conduction speed of the waves, disruption of entrained contractions and impaired lymph pump function. Our results point to defects in the lymphatic valve system rather than contraction wave dyssynchrony, as the mechanism underlying Cx43 and Cx47-related lymphedema and identify Cx45 as the connexin isoform mediating the entrainment of lymphatic contraction waves.

Chairperson: Helge Wiig, Department of Biomedicine