Endothelial Functions

Abstract

e108T he endothelium plays important roles in modulating vascular tone by synthesizing and releasing an array of endothelium-derived relaxing factors, including vasodilator prostaglandins, NO, and endothelium-dependent hyperpolarization (EDH) factors, as well as endothelium-derived contracting factors.1,2 Such redundant mechanisms, like endogenous hyperglycemic hormones, are advantageous for ensuring proper maintenance of vascular tone under pathological conditions, where one of the vasoactive factor-mediated responses is compromised favoring a vasoconstrictor, prothrombotic, and proinflammatory state. Endothelial dysfunction is mainly caused by reduced production or action of endothelium-derived relaxing factors and could be an initial step toward cardiovascular disease.1 Indeed, evaluation of endothelial functions in humans has attracted much attention in the clinical settings because it serves as an excellent surrogate marker of cardiovascular events. For instance, endothelial dysfunction, as evaluated by impaired flow-mediated dilation of the brachial artery or digital reactive hyperemia index in peripheral arterial tonometry, is associated with future cardiovascular events in patients with coronary artery disease, 3-5 and 1-SD decrease in flow-mediated dilation or reactive hyperemia index is associated with doubling of cardiovascular event risk. 6 These observations suggest that endothelial function in peripheral vascular beds could predict future cardiovascular events.In this review, we will sum up the current advances and trends in the research on endothelial functions from bench to bedside with particular focus on recent publications in Arteriosclerosis, Thrombosis, and Vascular Biology. Earlier highlights of the journal on endothelial biology are extensively summarized in some review articles. 7-9 Emerging Modulators of Endothelial Functions Shear StressAs Lüscher and Corti 10 described in an editorial, flow is the signal of life. This physical force is sensed by the endothelium lining internal surface of the whole cardiovascular system to be translated into numerous downstream signaling pathways in a moment to moment manner in response to diverse physiological demands in the body. Indeed, shear stress is one of the important physiological cues that make endothelial cells synthesize and release endothelium-derived relaxing factors to cause relaxation of underlying vascular smooth muscle and vasodilatation. In this context, novel mechanisms of endothelial mechanotransduction in health and disease have been unveiled and summarized in a review series published recently in Arteriosclerosis, Thrombosis, and Vascular Biology. 11,12 Briefly, Zhou et al 12 emphasized the distinct roles of atheroprotective laminar or pulsatile shear stress versus atheroprone oscillatory shear stress or disturbed flow and discussed in detail the underlying molecular mechanisms that are dependent on these patterns of flow. Abe and Berk 11 further reviewed the current knowledge on the dual roles of shear stress with emphasis plac...

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

“…In agreement with that, isolated arterioles from animals/humans showed NO-dependent dilation under PS or SS; OS did not induce dilation [157,158]. PS (or SS) was found to trigger EC secretion of ATP causing autocrine/paracrine activation of surface purinergic receptors (G q /G 11 protein-coupled P2Y 2 Rs), activation of PLC, generation of IP 3 The pro-inflammatory signalling pathways underlying atherogenesis, including c-Jun N-terminal kinase (JNK)/the family of mitogen-activated protein kinases (MAPKs) and the transcription factors NF-kB and activator protein-1 (AP-1), are redox sensitive [181]. OS was found to cause a sustained increase in O 2 Á2 production/ROS levels, whereas PS (or SS)…”

“…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 ).…”

Thrombotic Regulation From the Endothelial Cell Perspectives

“…Loss of endothelial normal function or structural integrity results in acute thrombosis, or chronic vascular changes that predispose to thrombosis among a variety of diseases, such as atherosclerosis, restenosis, diabetes mellitus, obesity, etc. [70][71][72][73] Understanding the mechanism by which endothelium regulates thrombosis not only provides insights into thrombosis mechanism and pathology of relevant diseases but also fuel the therapeutic endeavor for discovering effective antithrombotic drugs with minimal or no bleeding risk, which constitute a substantial unmet medical need.…”

Preserved cardiovascular homeostasis despite blunted acetylcholine‐induced dilation in mice with endothelial muscarinic M3 receptor deletion

“…7,8 Despite the fact that this sequence of events upon AChMR stimulation is well established the physiologic relevance remains elusive and the function of endothelial AChMR is still mysterious. The gold standard to stimulate the endothelium is application of the neurotransmitter acetylcholine (ACh), which acts through AChMR to activate G q proteins and consequently phospholipase C that elicits an intracellular calcium increase mainly through release from stores.…”