Connexins in endothelial barrier function – novel therapeutic targets countering vascular hyperpermeability

Abstract

SummaryProlonged vascular hyperpermeability is a common feature of many diseases. Vascular hyperpermeability is typically associated with changes in the expression patterns of adherens and tight junction proteins. Here, we focus on the less-appreciated contribution of gap junction proteins (connexins) to basal vascular permeability and endothelial dysfunction. First, we assess the association of connexins with endothelial barrier integrity by introducing tools used in connexin biology and relating the findings to customary readouts in vascular biology. Second, we explore potential mechanistic ties between connexins and junction regulation. Third, we review the role of connexins in microvascular organisation and development, focusing on interactions of the endothelium with mural cells and tissue-specific perivascular cells. Last, we see how connexins contribute to the interactions between the endothelium and components of the immune system, by using neutrophils as an example. Mounting evidence of crosstalk between connexins and other junction proteins suggests that we rethink the way in which different junction components contribute to endothelial barrier function. Given the multiple points of connexin-mediated communication arising from the endothelium, there is great potential for synergism between connexin-targeted inhibitors and existing immune-targeted therapeutics. As more drugs targeting connexins progress through clinical trials, it is hoped that some might prove effective at countering vascular hyperpermeability.

Endothelial connexins in vascular function

“…Disruption of the endothelial barrier function resulting in increased vascular permeability is a key event in pathological conditions associated with edema and inflammation. Although the endothelial barrier is principally regulated by tight junctions (TJs) sealing the intercellular space and adherens junctions (AJs) providing mechanical anchorage (36), recent evidence suggests that GJs and/or Cxs may play a role in the regulation of the endothelial barrier function as well (37).…”

α1AMP-Activated Protein Kinase Protects against Lipopolysaccharide-Induced Endothelial Barrier Disruption via Junctional Reinforcement and Activation of the p38 MAPK/HSP27 Pathway

“…Other constituents play major roles in the organization of protein-protein complexes in plasma membranes. They include connexin 43 (Cx43), which can directly and indirectly affect TJ and AJ assembly [15][16][17]. Actually, Cx43 signaling microdomains can influence a wide range of junctional-and cytoskeleton-associated proteins [18,19] through mechanisms that involve direct protein-protein interactions and transcriptional regulation [19][20][21].…”

Leptospira interrogans causes quantitative and morphological disturbances in adherens junctions and other biological groups of proteins in human endothelial cells

“…A gap junction is formed as junctional channels between neighboring cells by oligomers of specific integral membrane proteins, such as connexins [ 74 , 75 ]. The gap junctional proteins play roles in subcellular microdomain signaling as well as the regulation of intercellular communication through passage of ions and small molecules [ 74 , 75 ]. The gap junction protein we examined is connexin 43, which is the most ubiquitously distributed of this class of proteins in mammalian cells [ 74 ].…”

“…In the immature cell junctions, ZO-1 can directly associate with alpha-catenin and the actin cytoskeleton [ 67 , 89 ] and indirectly associates with beta-catenin [ 90 ]. In the mature tight junction, ZO-1 indirectly influences the endothelial integrity via association with claudin, occuldin, and actin filaments [ 60 , 75 ]. The published information and our data imply that Leptospira primarily disrupts the adherens junctions, resulting in mislocalization of one of the actin-binding proteins, ZO-1 ( Fig 7 ).…”

“…The non-pathogenic Patoc strain caused translocation of connexin 43 from the cell periphery to intracellular locations without losing signal intensity ( Fig 5B ). Connexin 43 associates with a variety of proteins located at adherens junctions and tight junctions, the cytoskeleton, and actin-binding proteins, including p120 catenin, beta-catenin, and ZO-1 [ 74 , 75 ]. Moreover, the gap junction is not directly involved in endothelial permeability [ 62 ].…”