Humoral and Mechanical Cross-Talk in the Vasculature: Perspectives in Vascular Disease

Blood vessels are continuously subjected to the action of mechanical forces in the form of shear stress and strain associated with stretch of the vessel wall. Shear stress results from the friction of blood against the lumen of the vessel and is sensed by endothelial cells. Strain is the major determinant of vessel stretch, to which a cyclic quantity is added stemming from the pulsatile nature of blood pressure. The mechanical stretch affects endothelial cells, smooth muscle cells and cells in the outer adventitial layer of the blood vessel. These mechanical forces are detected by mechanosensors which initiate a variety of signaling system cascades responsible for triggering functional responses unique for a particular cell type. Although many of the pathophysiological effects resulting from mechanical stimulation have been described for vascular cells, identity of the mechanosensor and associated transduction mechanisms remain to be determined. The cellular reaction to shear stress and circumferential stretching also depends on other factors, such as stretch-induced secretion of humoral growth factors and effects on cell-cell junctions, some of which might be triggered directly while others are secondary to the adhesion-mediated response. This article discusses key aspects of mechanical signaling and how these mechanisms may regulate and cross-talk with humoral systems in the development of vascular disease. This includes the potential role of integrinextracellular matrix interactions, focal adhesions, ion-channels, the cytoskeleton, mitogen-activated protein kinases, GTP-binding proteins and interaction of these components to form various signaling complexes. Although the vascular system is emphasized, the signal transduction systems presented have similar functions in other tissues. Future progress in the cardiovascular field will require identification of the mechanosensor(s) and associated signaling cascades which synergize with humoral systems that ultimately lead to structural and functional abnormalities.