PATHWAYS CONTROLLING HEALTHY AND DISEASED ARTERIAL SMOOTH-MUSCLE

The cells within the vascular wall act as a unit regulating the contra ction of smooth muscle cells. In arteries the endothelium and autonomi c nerves provide the major factors that regulate intracellular calcium in smooth muscle cells, which determines contractile tone. The endoth elium provides a major inhibitory influence, which itself is modulated by shear forces within the vascular lumen regulating endothelial cell calcium and the release of endothelium-derived relaxing factors. Of t he major mechanisms controlling smooth muscle calcium, it has been sug gested that voltage-dependent calcium channels are among the most impo rtant in mediating the inhibitory influence of the endothelium. Smooth muscle potassium channels and sodium-potassium adenosine triphosphata se (Na+,K+-ATPase) are important regulators of membrane potential, and each is affected by the endothelium. Because the activity of each hyp erpolarizes the membrane potential, they counter the influence on volt age-dependent calcium channels and inhibit contraction. Both of these counterregulatory mechanisms have recently been shown to be impaired i n diseased arteries. This may help to explain the diminished effective ness of the endothelium on the smooth muscle. Thus, vascular disease m ay cause diminished release, increased destruction, or limited effecti veness of endothelium-derived relaxing factors. The failure of the inh ibitory influence of the endothelium may be the principal mechanism by which vascular risk factors and disease increase vasoconstrictor tone , possibly contributing to hypertension and the progression of atheros clerosis.