Evolving mechanisms of vascular smooth muscle contraction highlight key targets in vascular disease

Abstract

Vascular smooth muscle (VSM) plays an important role in the regulation of vascular function. Identifying the mechanisms of VSM contraction has been a major research goal in order to determine the causes of vascular dysfunction and exaggerated vasoconstriction in vascular disease. Major discoveries over several decades have helped to better understand the mechanisms of VSM contraction. Ca has been established as a major regulator of VSM contraction, and its sources, cytosolic levels, homeostatic mechanisms and subcellular distribution have been defined. Biochemical studies have also suggested that stimulation of Gq protein-coupled membrane receptors activates phospholipase C and promotes the hydrolysis of membrane phospholipids into inositol 1,4,5-trisphosphate (IP) and diacylglycerol (DAG). IP stimulates initial Ca release from the sarcoplasmic reticulum, and is buttressed by Ca influx through voltage-dependent, receptor-operated, transient receptor potential and store-operated channels. In order to prevent large increases in cytosolic Ca concentration ([Ca]), Ca removal mechanisms promote Ca extrusion via the plasmalemmal Ca pump and Na/Ca exchanger, and Ca uptake by the sarcoplasmic reticulum and mitochondria, and the coordinated activities of these Ca handling mechanisms help to create subplasmalemmal Ca domains. Threshold increases in [Ca] form a Ca-calmodulin complex, which activates myosin light chain (MLC) kinase, and causes MLC phosphorylation, actin-myosin interaction, and VSM contraction. Dissociations in the relationships between [Ca], MLC phosphorylation, and force have suggested additional Ca sensitization mechanisms. DAG activates protein kinase C (PKC) isoforms, which directly or indirectly via mitogen-activated protein kinase phosphorylate the actin-binding proteins calponin and caldesmon and thereby enhance the myofilaments force sensitivity to Ca. PKC-mediated phosphorylation of PKC-potentiated phosphatase inhibitor protein-17 (CPI-17), and RhoA-mediated activation of Rho-kinase (ROCK) inhibit MLC phosphatase and in turn increase MLC phosphorylation and VSM contraction. Abnormalities in the Ca handling mechanisms and PKC and ROCK activity have been associated with vascular dysfunction in multiple vascular disorders. Modulators of [Ca], PKC and ROCK activity could be useful in mitigating the increased vasoconstriction associated with vascular disease.

Clinacanthus nutans Leaves Extract Reverts Endothelial Dysfunction in Type 2 Diabetes Rats by Improving Protein Expression of eNOS

“…Phenylephrine, an α -adrenergic receptor agonist stimulates Ca 2+ entry through voltage-gated and store-operated Ca 2+ channels and activates Ca 2+ sensitization pathways such as protein kinase-C (PKC) and Rho-kinase [ 36 ]. Activation of PKC increases the myofilament force sensitivity to cytosolic Ca 2+ concentration and myosin light-chain (MLC) phosphorylation and thereby maintains VSMC contraction with smaller increases in cytosolic Ca 2+ concentration [ 37 ]. In this study, PE-induced endothelium-independent contraction was increased in the thoracic aorta of untreated diabetic rats compared to the nondiabetic controls.…”

Dietary fish oil supplement induces age-specific contractile and proteomic responses in muscles of male rats

“…An alternative possibility is that DFO increases myosin light chain (MLC) phosphorylation, the primary mechanism for contractile potentiation in skeletal muscle [ 47 ]. As smooth muscle contraction is highly dependent on MLC phosphorylation [ 48 ], such a mechanism could possibly account for both our results and those described in smooth muscle, though this is highly speculative and has not yet been investigate.…”

“…b) Representative immunoblots with the identical standard for corresponding proteins in A along with the corresponding GAPDH loading blots [47]. As smooth muscle contraction is highly dependent on MLC phosphorylation [48], such a mechanism could possibly account for both our results and those described in smooth muscle, though this is highly speculative and has not yet been investigate.…”

Sphingosine-1-Phosphate Enhances α1-Adrenergic Vasoconstriction via S1P2–G12/13–ROCK Mediated Signaling

“…This conclusion is supported by our observations that the potentiating effect of S1P is absent in the absence of S1P2 receptors or G 12/13 proteins and can be abolished by the ROCK inhibitor Y-27632 and fasudil. Therefore, it is most likely that S1P treatment via activation of the ROCK pathway inhibits myosin phosphatase leading to a maintained state of myosin phosphorylation [62,63].…”