Symphony of Vascular Contraction

Abstract

The principle functions of arterial smooth muscle cells include contraction, relaxation, and growth. Calcium signaling mechanisms govern the main functions of arterial smooth muscle and trigger specific responses.1–3 Cytosolic calcium concentrations and calcium signals are finely tuned by intracellular sources such as the sarcoplasmic reticulum, calcium-binding proteins, and plasma membrane calcium permeable channels. In hypertension, these mechanisms are substantially modified, promoting a hypercontractile state and arterial wall remodeling. In this review, we will discuss various elements that are central to intracellular calcium handling and signaling in arterial smooth muscle cells. Emphasis will be given to most recent discoveries of components that link intracellular calcium stores to plasma membrane calcium entry channels. In addition, we will propose a novel paradigm, suggesting that in hypertension, alarm signals generated by chronic innate immune system activation and transduced by pattern recognition receptors modulate calcium signaling mechanisms in arterial smooth muscle, promoting vascular dysfunction. Finally, new research directions in the context of calcium signaling in hypertension will be addressed. Arterial smooth muscle contraction is regulated by receptor or mechanical activation of the contractile proteins actin and myosin.4 Changes in the membrane potential can also initiate contraction. The phosphorylation state of the light chain of myosin determines the contractile activity of arterial smooth muscle. Specifically, for contraction to occur, myosin light chain (MLC) kinase must phosphorylate Ser 19 of the 20-kDa regulatory MLC, enabling the interaction between myosin and actin.5,6 The cycling of the myosin cross-bridges with actin is promoted by energy released from ATP by myosin ATPase activity.7,8 In some arteries, MLC is in a phosphorylated state in the absence of any external stimuli (ie, vascular smooth muscle tone). An increase in cytosolic calcium concentration is the trigger for vascular contraction.9 Hypertensive patients and …