Endothelial connexins in vascular function

Abstract

Gap junctions are essential for intercellular crosstalk in blood and lymphatic vasculature. These clusters of intercellular channels ensure direct communication among endothelial cells and between endothelial and smooth muscle cells, and the synchronization of their behavior along the vascular tree. Gap junction channels are formed by connexins; six connexins form a connexon or hemichannel and the docking of two connexons result in a full gap junction channel allowing for the exchange of ions and small metabolites between neighboring cells. Recent evidence indicates that the intracellular domains of connexins may also function as an interaction platform (interactome) for other proteins, thereby regulating their function. Interestingly, fragments of Cx proteins generated by alternative internal translation were recently described, although their functions in the vascular wall remain to be uncovered. Variations in connexin expression are observed along different types of blood and lymphatic vessels; the most commonly found endothelial connexins are Cx37, Cx40, Cx43 and Cx47. Physiological studies on connexin-knockout mice demonstrated the essential roles of these channel-forming proteins in the coordination of vasomotor activity, endothelial permeability and inflammation, angiogenesis and in the maintenance of fluid balance in the body.

Keywords: connexin; endothelium; gap junction; intercellular communication.

Figure 1

Synthesis and trafficking of Cxs. After translation, Cxs are inserted in the endoplasmic reticulum (ER) and then assemble into hexameric connexons in the ER or Golgi apparatus. Connexons travel across microtubules to the cell surface where these hemichannels remain closed or may be opened in response to pathological stimuli. Connexons from adjacent cells pair to form GJ channels allowing the direct exchange of ion or metabolites between both cells. Alternative internal translation of the GJA1 gene transcript (encoding for Cx43) produces a 20 kDa fragment representing the C-terminal 169 amino acids of the protein. GJA1-20 kDa has been shown to stabilize actin filaments to guide full-length Cx43 delivery to the plasma membrane, to facilitate microtubule-based mitochondrial transport, and it has been shown to translocate to the nucleus of cells.

Figure 2

Endothelial Cx43 expression is increased in arterial regions exposed to disturbed flow. (A) Schematic representation of arterial regions exposed to unidirectional and disturbed flow. (B) En face immunostainings of Cx43 (in green) in mouse arterial endothelium of the common carotid artery (b) and at the carotid bifurcation (C). Nuclei are stained with DAPI (in blue). Scare bar represents 30 µm.