Endothelial Permeability: Paracellular Pathway vs. Transcellular Pathway
Sponsored by the APS Cell & Molecular Physiology Section

The vascular endothelium is formed by a sheet of endothelial cells tethered to a network of extracellular matrices.  Aberration of endothelial barrier function leads to an abnormal extravasation of blood components and accumulation of fluid in the extravascular space, resulting in tissue dysfunction.  This injurious process has been implicated in inflammation, trauma, sepsis, ischemia-reperfusion, diabetes, atherosclerosis., tumor development and metastasis. Research efforts over the past few decades have been focused on the paracellular pathway of endothelial permeability, where a dynamic interaction between the endothelial contractile cytoskeleton and cell-cell adhesive junction is known to control the transendothelial flux of fluid and macromolecules.  In addition, focal adhesion-mediated endothelial cell-matrix tethering is essential to the maintenance of endothelial barrier integrity and also contributes to the hyperpermeability response to inflammation and angiogenesis. Multiple signaling molecules have been identified in the upstream of pathways that trigger the structural changes in endothelial barrier, of which tremendous controversy resides on the permeability effect of nitric oxide and its mechanism of action.  On the other hand, the conventional concept regarding the critical role of intercellular gap formation in vascular leakage has recently met with a great challenge.  Evidence is emerging to support a role for the transcellular pathway in mediating macromolecular transport across the endothelium.  In particular, gp60-dependent albumin transcytosis and protein transport via caveolae, vesicles or other intracellular organelles have been reported.  However, whether such mechanisms contribute to the endothelial hyperpermeability response under stimulated conditions remains to be an interesting issue. Further investigation to establish the relative importance of the transcellular vs. paracellular pathways in the physiological and pathological regulation of microvascular permeability represents a future direction of research in this area.