Novel regulators of endothelial barrier function

Abstract

Endothelial barrier function is an essential and tightly regulated process that ensures proper compartmentalization of the vascular and interstitial space, while allowing for the diffusive exchange of small molecules and the controlled trafficking of macromolecules and immune cells. Failure to control endothelial barrier integrity results in excessive leakage of fluid and proteins from the vasculature that can rapidly become fatal in scenarios such as sepsis or the acute respiratory distress syndrome. Here, we highlight recent advances in our understanding on the regulation of endothelial permeability, with a specific focus on the endothelial glycocalyx and endothelial scaffolds, regulatory intracellular signaling cascades, as well as triggers and mediators that either disrupt or enhance endothelial barrier integrity, and provide our perspective as to areas of seeming controversy and knowledge gaps, respectively.

N-cadherin coordinates AMP kinase-mediated lung vascular repair

“…Our present studies build on previous work which supports the idea of location-dependent function and unique pools of AMPK (32). In lung capillary endothelium, AMP-activated kinase ␣1 (AMPK␣1) is both found in the cytosol and associated with the cell membrane.…”

“…Activation of AMPK␣1 was necessary for reestablishment of the endothelial barrier in response to LPS-induced damage and for resolution of LPS-induced pulmonary edema and increased permeability in vivo (11,24,32). Our current data provide evidence that AMPK␣1 function is linked to N-cadherin through the cadherin's cytoplasmic tail and that this interaction is necessary for AMPK␣1-mediated pulmonary response to endothelial injury.…”

Claudins: Gatekeepers of lung epithelial function

“…However, pulmonary microvascular endothelial cell tight junctions also contribute to alveolar barrier function by maintaining a tight seal to prevent leakage from the bloodstream. Failure of the microvascular barrier while the alveolar epithelial barrier is maintained leads to tissue edema [12, 13], whereas failure of the alveolar epithelial barrier causes airspace flooding and increases susceptibility to acute respiratory distress syndrome (ARDS) [14]. Besides the prevention of fluid leak, alveolar epithelial cells maintain lung fluid balance by regulating ion transport to promote fluid resorption, comparable to conducting airway epithelium [15–17].…”

Inter-α inhibitor protein and its associated glycosaminoglycans protect against histone-induced injury

“…Similarly, mutant CHO cells that lack a key enzyme of the biosynthesis pathway of all GAGs 29 were more vulnerable to histones than the wild-type CHO cells, strongly supporting the protective role of cell surface glycocalyx in neutralizing extracellular histones. It is known that glycocalyx plays major protective roles in the homeostasis of the vessel wall, 52 and its degradation during sepsis leads to shedding of proteoglycans and/or GAGs. 53 Thus, circulating amounts of GAGs are high in patients with sepsis, 54 and increased plasma levels of syndecan-1 54 and heparan sulfate 55 have been correlated with disease severity.…”