INTRACELLULAR SIGNALING AND VASCULAR TONE

The main function of vascular smooth muscle tissue is the regulation o f blood pressure through changes in the vascular tone. Two main factor s regulate the contraction and relaxation of vascular smooth muscle ce lls: the cytosolic free Ca2+ concentration ([Ca2+](i)) and the Ca2+ se nsitivity of the contractile elements. Schematically, constrictors inc rease [Ca2+](i) and the Ca2+ sensitivity of contractile apparatus whil e relaxant agonists have opposite effects, The sources of Ca2+ are bot h extracellular and intracellular. The sarcoplasmic reticulum (SR) is the physiological intracellular source of Ca2+. The Ca2+ storage capac ity of SR involves intraluminal Ca2+ binding protein such as calseques trin and calreticulin. Ca2+ is released from SR to the cytosol through InsP(3) and ryanodine receptors (InsP(3)-induced Ca2+ release and Ca2 +-induced Ca2+ release), During relaxation, the [Ca2+], is reduced in part by Ca2+ pumping into the Sn by Ca2+-ATPase (SERCA). Several isofo rms of SERCA are expressed in vascular smooth muscle, Ca2+ enters into vascular smooth cells through Ca2+ permeable ion channels. The capaci tative Ca2+ entry and ligand-gated channels (P-2 kappa-purinoceptors) allow extracellular Ca2+ to flow into the cytosol. However, voltage-de pendent Ca2+ channels represent the main route for Ca2+ entry which is essentially modulated by the membrane potential. Ca2+-activated chann els such as Cl- (Cl-Ca) or K+ (K-ca) channels play a key role in the m odulation of membrane potential. Activated Cl-cd channels depolarize w hereas activated K-ca channels hyperpolarize the membrane thus causing increase and decrease in the vascular tone, respectively, Modulation of the force at constant [Ca2+](i) results from charges in the activit ies of kinases and phosphatases, acting on the regulatory light chain of myosin (MLC20) phosphorylation. Intracellular messengers such as ar achidonic acid or protein kinase modulate the activity of the MLC20 ph osphatase and thus, the Ca2+ sensitivity. G protein-coupled Ca2+ sensi tization also involves inhibition of the MLC20 phosphatase. Trimeric a s well as monomeric G proteins (Rho p(21), Ras p(21)) seem to be respo nsible for this mechanism. Recent studies, by identifying new regulato ry mechanisms, provide a better understanding of the funda mental mech anisms regulating contractile properties of vascular smooth muscle and open new way for the treatment of vascular diseases.