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1.
Cell Mol Life Sci ; 78(1): 31-61, 2021 Jan.
Article in English | MEDLINE | ID: mdl-32594191

ABSTRACT

Diabetes affects millions of people worldwide. This devastating disease dramatically increases the risk of developing cardiovascular disorders. A hallmark metabolic abnormality in diabetes is hyperglycemia, which contributes to the pathogenesis of cardiovascular complications. These cardiovascular complications are, at least in part, related to hyperglycemia-induced molecular and cellular changes in the cells making up blood vessels. Whereas the mechanisms mediating endothelial dysfunction during hyperglycemia have been extensively examined, much less is known about how hyperglycemia impacts vascular smooth muscle function. Vascular smooth muscle function is exquisitely regulated by many ion channels, including several members of the potassium (K+) channel superfamily and voltage-gated L-type Ca2+ channels. Modulation of vascular smooth muscle ion channels function by hyperglycemia is emerging as a key contributor to vascular dysfunction in diabetes. In this review, we summarize the current understanding of how diabetic hyperglycemia modulates the activity of these ion channels in vascular smooth muscle. We examine underlying mechanisms, general properties, and physiological relevance in the context of myogenic tone and vascular reactivity.


Subject(s)
Hyperglycemia/pathology , Ion Channels/metabolism , Muscle, Smooth, Vascular/metabolism , Animals , Calcium Channels/metabolism , Cyclic AMP-Dependent Protein Kinases/metabolism , Diabetes Mellitus/metabolism , Diabetes Mellitus/pathology , Endothelial Cells/metabolism , Glucose/metabolism , Humans , Hyperglycemia/metabolism
2.
Vascul Pharmacol ; 132: 106776, 2020 09.
Article in English | MEDLINE | ID: mdl-32707323

ABSTRACT

Phosphatidylinositol 4,5-bisphosphate (PIP2) acts as substrate and unmodified ligand for Gq-protein-coupled receptor signalling in vascular smooth muscle cells (VSMCs) that is central for initiating contractility. The present work investigated how PIP2 might perform these two potentially conflicting roles by studying the effect of myristoylated alanine-rich C kinase substrate (MARCKS), a PIP2-binding protein, on vascular contractility in rat and mouse mesenteric arteries. Using wire myography, MANS peptide (MANS), a MARCKS inhibitor, produced robust contractions with a pharmacological profile suggesting a predominantly role for L-type (CaV1.2) voltage-gated Ca2+ channels (VGCC). Knockdown of MARCKS using morpholino oligonucleotides reduced contractions induced by MANS and stimulation of α1-adrenoceptors and thromboxane receptors with methoxamine (MO) and U46619 respectively. Immunocytochemistry and proximity ligation assays demonstrated that MARCKS and CaV1.2 proteins co-localise at the plasma membrane in unstimulated tissue, and that MANS and MO reduced these interactions and induced translocation of MARCKS from the plasma membrane to the cytosol. Dot-blots revealed greater PIP2 binding to MARCKS than CaV1.2 in unstimulated tissue, with this binding profile reversed following stimulation by MANS and MO. MANS evoked an increase in peak amplitude and shifted the activation curve to more negative membrane potentials of whole-cell voltage-gated Ca2+ currents, which were prevented by depleting PIP2 levels with wortmannin. This present study indicates for the first time that MARCKS is important regulating vascular contractility and suggests that disinhibition of MARCKS by MANS or vasoconstrictors may induce contraction through releasing PIP2 into the local environment where it increases voltage-gated Ca2+ channel activity.


Subject(s)
Calcium Channels, L-Type/metabolism , Muscle, Smooth, Vascular/metabolism , Myristoylated Alanine-Rich C Kinase Substrate/metabolism , Phosphatidylinositol 4,5-Diphosphate/metabolism , Vasoconstriction , Animals , Calcium Channel Blockers/pharmacology , Calcium Channels, L-Type/drug effects , Mesenteric Artery, Superior/metabolism , Mice, 129 Strain , Muscle, Smooth, Vascular/drug effects , Myristoylated Alanine-Rich C Kinase Substrate/antagonists & inhibitors , Myristoylated Alanine-Rich C Kinase Substrate/genetics , Peptide Fragments/pharmacology , Rats, Wistar , Signal Transduction , Vasoconstriction/drug effects , Vasoconstrictor Agents/pharmacology
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