Researchers have discovered the important role of plakoglobin (PG) in regulating the integrity of the endothelial barrier, which is pivotal for maintaining vascular function. Recent studies indicate PG not only serves as a structural component of endothelial junctions but also interacts with various signaling molecules to modulate vascular permeability.<\/p>
The endothelium, the thin layer of cells lining blood vessels, acts as a selective barrier, controlling the movement of substances between the bloodstream and surrounding tissues. Disruption of this barrier can lead to severe complications, including inflammation and edema. The study focused on myocardial endothelial cells derived from both wild type (WT) and PG knockout (PG-KO) mice to analyze the effects of PG absence on endothelial barrier function.
Under basal conditions, transendothelial electrical resistance (TEER) measurements revealed significantly enhanced barrier function in PG-KO cells compared to WT. This increase was associated with elevated levels of junctional proteins such as VE-cadherin and beta-catenin at cell junctions, which play key roles in cell adhesion and barrier stability.
"Surprisingly, the loss of PG resulted in unexpected enhancements of endothelial barrier integrity, indicating its dual role as both structural and signaling molecule," wrote the authors of the article. The researchers noted distinct differences in the localization of cortactin, another actin-binding protein, highlighting PG's potential role in stabilizing cellular junctions.
The study also evaluated the intracellular levels of cyclic adenosine monophosphate (cAMP)—a key second messenger involved in various signaling pathways, including those controlling endothelial barrier function. Researchers observed reduced basal cAMP levels in PG-KO cells compared to WT; yet, both cell types responded similarly when treated with agents to increase cAMP levels, such as Forskolin and Rolipram. This response corroborated the long-standing notion of cAMP's influence on endothelial barrier dynamics.
Upon increasing cAMP levels, both WT and PG-KO cells exhibited enhanced TEER, but the response was more pronounced in WT cells, indicating PG's partial involvement in cAMP-mediated barrier tightening. "The findings suggest PG is not strictly necessary for cAMP-induced endothelial barrier enhancement but does influence the sensitivity of the barrier to cAMP fluctuations," the authors noted.
Further analyses revealed the activity of small GTPases, Rac1 and RhoA, remained unaltered between the two cell lines, emphasizing PG's minimal role in their activation. These results indicate the potential complexity of signaling pathways dependent on PG's presence, where compensatory mechanisms might function to maintain barrier integrity even when PG is absent.
Overall, the research sheds light on the multifaceted role of PG within endothelial cells. Although its absence leads to improved barrier integrity through compensated adhesion molecule expression, it also reduces the basal cAMP levels and the ability of cells to respond to cAMP signaling. Such insights pave the way for new therapeutic strategies aimed at enhancing endothelial barrier function during various pathological conditions.