These studies support the possibility that negatively charged proteins of intermediate size could traverse the endothelial cells only if there were a decrease in the net negative charge of the microvessel walls. It is therefore interesting that an increased blood flow appears to result in a decrease in negative surface charge at the luminal endothelial surface of rat intestinal mucosal capillaries. Alternatively, it has been reported that inflammatory agents released upon the LH surge bind specific receptors, causing a cascade of cell signals that reorganize molecules at interendothelial junctions to increase permeability. These inflammatory agents act by inducing increases in intracellular calcium and tyrosine phosphorylation that lead to changes in the distribution of cell-to-cell adhesion molecules such as cadherins, catenins, and integrins, thus decreasing cell-to-cell or cell-to-extracellular matrix attachment. This decreased cellular attachment would increase the interendothelial gap distance, thus increasing permeability.
Lastly, increased permeability has also been attributed to the contraction of endothelial cells. LH-stimulated increases in inflammatory agents such as histamine, for example, have been implicated in regulating this endothelial contractile mechanism. Majno et al. found that rat vascular endothelial cells contracted when histamine levels were increased and that the contraction caused the formation of intercellular gaps. Two possible pathways have been implicated in permeability modulation by histamine. buy prednisone
The first is characterized by the binding of histamine and stimulation of inositol phosphate synthesis. This results in the mobilization of intracellular calcium, causing myosin-actin contraction and intercellular gap formation. Another pathway is characterized by histamine binding and stimulation of the synthesis of NO via a phospholipase C-initiated pathway, resulting in an increase in cGMP, which interacts with the cytoskeletal components, causing the formation of intercellular gaps. The basis for regulation of permeability by endothelial contraction may involve the presence of fibrous chains of membrane glycoproteins and absorbed plasma proteins that are located between the endothelial cells. The matrix acts as a molecular sieve so that when the endothelial cells contract, the matrix is stretched or even reorganized to create larger openings for the trans-barrier flux of serum proteins.