Calcium and Endothelium-Mediated Vasodilator Signaling

Abstract

Vascular tone refers to the balance between arterial constrictor and dilator activity. The mechanisms that underlie tone are critical for the control of haemodynamics and matching circulatory needs with metabolism, and thus alterations in tone are a primary factor for vascular disease etiology. The dynamic spatiotemporal control of intracellular Ca(2+) levels in arterial endothelial and smooth muscle cells facilitates the modulation of multiple vascular signaling pathways. Thus, control of Ca(2+) levels in these cells is integral for the maintenance of tone and blood flow, and intimately associated with both physiological and pathophysiological states. Hence, understanding the mechanisms that underlie the modulation of vascular Ca(2+) activity is critical for both fundamental knowledge of artery function, and for the development of targeted therapies. This brief review highlights the role of Ca(2+) signaling in vascular endothelial function, with a focus on contact-mediated vasodilator mechanisms associated with endothelium-derived hyperpolarization and the longitudinal conduction of responses over distance.

AKAP150-dependent cooperative TRPV4 channel gating is central to endothelium-dependent vasodilation and is disrupted in hypertension

“…Muscarinic receptors [the M3 subtype in ECs (5)], and other G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptors (GPCRs) that signal through Gα q , stimulate phospholipase C (PLC) to produce IP 3 and diacylglycerol (DAG), which in turn activate IP 3 Rs and PKC, respectively. To determine whether CCh stimulation of TRPV4 sparklets occurred through the GPCR-Gα q -PLC-DAG-PKC pathway in ECs, we tested the effects of pharmacological inhibition of PLC and activation of PKC.…”

“…Increased intracellular Ca 2+ concentrations activate Ca 2+ -sensitive molecular targets, including endothelial nitric oxide synthase (eNOS) (15), phospholipase A 2 (16), and small- and intermediate-conductance Ca 2+ -sensitive potassium (SK and IK) channels (17, 18). Whereas activation of the first two pathways promotes vasodilation through the production of soluble vasodilators—nitric oxide (NO) and cyclooxygenase (COX) products, respectively—engagement of the third channel-mediated mechanism leads to endothelium-dependent hyperpolarization (EDH), which spreads through gap junctions in specialized EC projections to adjacent smooth muscle cells (SMCs) called myoendothelial projections (MEPs), causing dilation of small resistance arteries and arterioles by decreasing the activity of voltage-dependent Ca 2+ channels (VDCCs) in SMCs (2, 5). Many of the molecular players involved in EDH-mediated vasodilation have been identified; however, their signaling linkages and the spatial organization of signaling complexes remain poorly understood.…”

Enhanced contractility in pregnancy is associated with augmented TRPC3, L-type, and T-type voltage-dependent calcium channel function in rat uterine radial artery

“…Regulation of vascular smooth muscle (SM) constriction is a primary determinant of vascular tone and is accompanied by changes in the intracellular SM [Ca 2ϩ ], modulated via the activity of ion channels, the sarcoplasmic reticulum Ca 2ϩ store, and the sensitivity of the contractile apparatus to intracellular [Ca 2ϩ ] (53). Calcium influx via voltage-dependent Ca 2ϩ channels (VDCC) and the nonvoltage-dependent channels from the transient receptor potential (TRP) family represent key pathways of intracellular Ca 2ϩ entry and Ca 2ϩ store refilling in the vasculature (47), with limited information on the role of these pathways in the uterine vasculature, and changes associated with pregnancy.…”

Mitochondrial Ca 2+ transport in the endothelium: regulation by ions, redox signalling and mechanical forces

“…Endothelial cell (EC) dysfunction has been implicated in the early stages of many cardiovascular diseases, which renders the modulation of EC functions a key therapeutic target [1][2][3]. Under normal conditions, EC functions depend on changes in the intracellular calcium concentration ([Ca 2þ ] i ).…”