Abstract
Hypertension is a major risk factor for many common chronic diseases, such as heart failure, myocardial infarction, stroke, vascular dementia, and chronic kidney disease. Pathophysiological mechanisms contributing to the development of hypertension include increased vascular resistance, determined in large part by reduced vascular diameter due to increased vascular contraction and arterial remodelling. These processes are regulated by complex-interacting systems such as the renin-angiotensin-aldosterone system, sympathetic nervous system, immune activation, and oxidative stress, which influence vascular smooth muscle function. Vascular smooth muscle cells are highly plastic and in pathological conditions undergo phenotypic changes from a contractile to a proliferative state. Vascular smooth muscle contraction is triggered by an increase in intracellular free calcium concentration ([Ca2+]i), promoting actin–myosin cross-bridge formation. Growing evidence indicates that contraction is also regulated by calcium-independent mechanisms involving RhoA-Rho kinase, protein Kinase C and mitogen-activated protein kinase signalling, reactive oxygen species, and reorganization of the actin cytoskeleton. Activation of immune/inflammatory pathways and non-coding RNAs are also emerging as important regulators of vascular function. Vascular smooth muscle cell [Ca2+]i not only determines the contractile state but also influences activity of many calcium-dependent transcription factors and proteins thereby impacting the cellular phenotype and function. Perturbations in vascular smooth muscle cell signalling and altered function influence vascular reactivity and tone, important determinants of vascular resistance and blood pressure. Here, we discuss mechanisms regulating vascular reactivity and contraction in physiological and pathophysiological conditions and highlight some new advances in the field, focusing specifically on hypertension.
Highlights
We showed that c-Src is a point of cross-talk between calcium- and oxidation/reduction-signalling in vascular cells and that in human hypertension, up-regulation of this system contributes to increased vascular [Ca2þ]i and contraction.[64]
In human vascular smooth muscle cells, Angiotensin II (Ang II) activates ROCK-mediated contractile signalling through the RhoA exchange factor Arhgef1.88 In addition to modulating vascular contraction in hypertension, ROCK activation is associated with increased vascular stiffness through processes that increase serum response factor (SRF)/myocardin signalling.[89]
Vascular contraction/relaxation is regulated by many processes that are both calcium-dependent and independent and involve calcium channels and signalling pathways such as IP3-protein kinase C (PKC)-DAG and ROCK
Summary
Hypertension is associated with vascular changes characterized by endothelial dysfunction, increased vascular contraction, and arterial remodelling.[1,2,3] Vascular smooth muscle cells, which constitute the bulk of the vascular wall, are critically involved in these processes through their highly plastic and dynamic features and ability to undergo phenotypic differentiation.[1,2,3] Pro-hypertensive stimuli, such as activation of the reninangiotensin-aldosterone system (RAAS), oxidative stress, activation of the sympathetic nervous system, haemodynamic changes, and mechanical forces stimulate vascular smooth muscle cell signalling, which promotes vasoconstriction, vascular hypertrophy, fibrosis, inflammation, and calcification, processes that underlie vascular functional, structural, and mechanical changes in hypertension.[4,5]. Small changes in lumen diameter have major impact on vascular resistance.[7] The lumen diameter of resistance arteries is a function of vasomotor tone (vasoconstriction/ vasodilation) and the structural and mechanical properties of the vessel. Acute regulation of vascular diameter and vascular resistance depends on the activation status of the contractile machinery involving actin: myosin interaction in vascular smooth muscle cells.[17] Changes in [Ca2þ]i, ion fluxes, and membrane potential lead to calcium– calmodulin-mediated phosphorylation of the regulatory myosin light chains (MLCs) and actin–myosin cross-bridge cycling with consequent rapid vasoconstriction.[18] Calcium-independent mechanisms associated with altered calcium sensitization and actin filament remodelling and increased bioavailability of reactive oxygen species (ROS) (oxidative stress), modulate vascular contraction.[19]. The role of vascular smooth muscle function in vascular remodelling, inflammation, and calcification and the importance of other vascular cell types in vascular health and disease are discussed elsewhere in the current issue of the journal
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