Vascular smooth muscle contraction in hypertension

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.

Figure 1

Calcium-dependent regulation of vascular smooth muscle cell (VSMC) contraction. Vasoconstrictors induce VSMC contraction by increasing the intracellular levels of Ca²⁺. Vasoactive peptides, such as Ang II, bind to G protein-coupled receptors (GPCRs) activating PLC leading to (i) production of IP₃ and (ii) formation of DAG. IP₃ binds to the IP receptor Ca²⁺ channel (InsP3R) and induces Ca²⁺ release from the sarcoplasmic reticulum (SR). DAG causes activation of PKC, which influences Ca²⁺ channels, such as store-operated Ca²⁺ channel (SOC), second messenger-operated Ca²⁺ channel (SMOC), receptor-operated Ca²⁺ channel (ROC), voltage-gated Ca²⁺ channel (VOC), and the Na⁺–Ca²⁺ exchanger (NCX). PKC also stimulates activity of the ryanodine Ca²⁺ channel (RyR) inducing release of Ca²⁺ from the SR. MLCP activity is reduced by CPI-17 phosphorylation. Ca²⁺ binds to calmodulin and activates the MLCK, leading to MLC20 phosphorylation at Ser19, actin polymerization, and vascular contraction.

Figure 2

ROCK-induced contraction of VSMCs. Vasoactive agents bind to their respective GPCRs leading to release of RhoA from a guanine nucleotide dissociation inhibitor (GDI). RhoA translocates to the membrane. Mechanisms involving RhoA activation also involve transactivation of receptor tyrosine kinases (RTKs). GEFs promote exchange of Guanosine diphosphate (GDP) to Guanosine triphosphate (GTP), activating the RhoA-ROCK pathway. Activated ROCK renders MLCP inactive by phosphorylation of CPI-17 and/or zipper-interacting protein (ZIPK), facilitating MLC20 phosphorylation and vascular contraction. Increased Ca²⁺ may directly activate ROCK through phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K)-dependent pathways.

Figure 3

VSMC contraction and oxidative stress. Nox-derived ROS influence cellular Ca²⁺ homeostasis and pro-contractile signalling. Calcium also influences Nox-derived ROS generation, through Nox5, a Ca²⁺-sensitive Nox isoform that produces ${\mathrm{O}}_2^{\text{−}}$. Nox4 activation leads to production of H₂O₂. High levels of ROS, cause oxidative modifications of Ca²⁺ channels, ryanodine receptors (RyR), actin, actin-binding proteins as well as TRP cation channel, subfamily M, Member 2 (TRPM2). TRPM2, a redox-sensitive Ca²⁺ channel indirectly activated by H₂O₂ through poly (ADP-ribose) polymerase (PARP) activation in the nucleus and consequent Adenosine diphosphate-ribose (ADPR) production. Once released to the cytosol, ADPR binds and activates TRPM2, stimulating Ca²⁺ influx. Dashed line indicates that reduced MLCP activity results in icreased MLC20 activation.