Endothelial cells have been shown to contain an elaborate microfilament system allowing active actin- and myosin-based cell contraction. In peripheral endothelium, activation of cell contraction and disturbance of junctional organization subsequently result in the induction of inter-endothelial gaps followed by enhanced paracellular endothelial permeability. An increased intracellular cAMP level in endothelial cells has been known to decrease the basal permeability properties of the barrier and attenuate the increase in permeability when the endothelial cells are exposed to inflammatory agents. AM, as an autocrine/paracrine hormone, is a potent stimulator of cAMP elevation in endothelial cells. AM can stabilize the barrier function of endothelial cells by a cAMP-dependent relaxation of the microfilament system, thereby preventing endothelial cell contraction and paracellular fluid flux.
Results on transgenic mice show the importance of AM in the regulation of microcirculation. Mice overexpressing AM in their vasculature have turned out to be resistant to lipopolysaccharide-induced shock. On the other hand, AM knockout homozygous mice die at mid-gestation with extreme hydrops fetalis and cardiovascular abnormalities including severe hemorrhages and pericardial effusions. These suggest a general role for AM as an endothelium-derived autocrine hormone in the regulation of endothelial permeability.
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