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, 3 (2), 84-95

Vascular Smooth Muscle Cell Signaling Mechanisms for Contraction to Angiotensin II and Endothelin-1

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Vascular Smooth Muscle Cell Signaling Mechanisms for Contraction to Angiotensin II and Endothelin-1

Brandi M Wynne et al. J Am Soc Hypertens.

Abstract

Vasoactive peptides, such as endothelin-1 and angiotensin II are recognized by specific receptor proteins located in the cell membrane of target cells. Following receptor recognition, the specificity of the cellular response is achieved by G-protein coupling of ligand binding to the regulation of intracellular effectors. These intracellular effectors will be the subject of this brief review on contractile activity initiated by endothelin-1 and angiotensin II.Activation of receptors by endothelin-1 and angiotensin II in smooth muscle cells results in phopholipase C (PLC) activation leading to the generation of the second messengers insitol trisphosphate (IP(3)) and diacylglycerol (DAG). IP(3) stimulates intracellular Ca(2+) release from the sarcoplasmic reticulum and DAG causes protein kinase C (PKC) activation. Additionally, different Ca(2+) entry channels, such as voltage-operated (VOC), receptor-operated (ROC), and store-operated (SOC) Ca(2+) channels, as well as Ca(2+)-permeable nonselective cation channels (NSCC), are involved in the elevation of intracellular Ca(2+) concentration. The elevation in intracellular Ca(2+) is transient and initiates contractile activity by a Ca(2+)-calmodulin interaction, stimulating myosin light chain (MLC) phosphorylation. When the Ca(2+) concentration begins to decline, Ca(2+)-sensitization of the contractile proteins is signaled by the RhoA/Rho-kinase pathway to inhibit the dephosphorylation of MLC phosphatase (MLCP) thereby maintaining force generation. Removal of Ca(2+) from the cytosol and stimulation of MLCP initiates the process of smooth muscle relaxation. In pathological conditions such as hypertension, alterations in these cellular signaling components can lead to an over stimulated state causing maintained vasoconstriction and blood pressure elevation.

Keywords: Rho-kinase; calcium channel; phosphoinositides; vasoactive peptides.

Figures

Figure 1
Figure 1. Overview of major contributors to vascular smooth muscle contraction
In smooth muscle, contraction is initiated by a Ca2+ mediated change in the thick filaments, or myosin. With myosin light chain phosphorylation, the actin and myosin filaments are capable of interacting. ATP hydrolysis is the source for force generation in smooth muscle; with contraction, inorganic phosphate leaves the myosin head. Relaxation occurs via the action of myosin light chain phosphatase, which de-phosphorylates myosin light chain, inactivating it.
Figure 2
Figure 2. Molecular mechanisms of smooth muscle contraction
Vascular smooth muscle contraction is the summation of myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP) activity. With receptor binding, an increase in intracellular Ca2+ occurs, both via channels located in the membrane and intracellular stores in the sarcoplasmic reticulum. The Ca2+ interacts with calmodulin, forming a Ca2+-calmodulin complex which activates MLCK. MLCK can then phosphorylate myosin light chain (MLC-P), allowing for the close interaction of the actin and myosin filaments for force generation. Relaxation occurs with MLCP dephosphorylating MLC. In some instances, force generation can be tonic; this is mediated in a Ca2+-independent manner. Rho-kinase becomes activated via the small, activated RhoA protein, which subsequently phosphorylates MLCP, rendering the enzyme inactive and incapable of de-phosphorylating MLC. In addition, PKC and Rho kinase work in concert to activate CPI-17, which inhibits MLCP. Thus, the vascular smooth muscle cannot relax and a tonix contraction occurs.
Figure 3
Figure 3. The concept of receptor-operated Ca2+ (ROC) channels, voltage-operated Ca2+ (VOC) channels and store-operated Ca2+ (SOC) channels
ROC channels are activated via receptor stimulation of G-protein coupled receptors (GPCRs) directly or through the production of second messengers such as IP3 or DAG. IP3 can then bind to and activate the IP3 receptor on the sarcoplasmic reticulum membrane, causing discharge and release of the stored Ca2+. The release of Ca2+ from the sarcoplasmic reticulum induces Cl- efflux or the influx of Na+ and Ca+ from the ROC channels, which can then activate VOC channels. The second messenger, IP3 activates the IP3 receptor on the sarcoplasmic reticulum membrane, causing discharge and release of the stored Ca2+. After Ca2+ depletion from the sarcoplasmic reticulum, the SOC channels are activated. A, agonist; DAG, diacylglycerol; G, G-protein; IP3, inositol 1,4,5-trisphosphate; IP3R, IP3 receptor; PIP2, phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; R, receptor; TK, tyrosine kinase.
Figure 4
Figure 4. New pathways in vascular smooth muscle signaling
Orai1 and STIM work together to function as Ca2+ sensors within the cell. Orai1 makes up the pore of the CRAC channel, allowing for Ca2+ entry while STIM1 senses Ca2+ levels within the SR. Their interaction facilitates this process. The IKCa channels are intermediate conductance Ca2+-activated K+ channels which are of importance in small resistance vessels. G12/13 signaling through LARG was recently found to be a mechanism for RhoA/Rho kinase activation, leading to MLCP inactivation.

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