Endothelial Function

Abstract

T he endothelium regulates vascular tone, platelet activity, leukocyte adhesion, and angiogenesis by producing nitric oxide and other regulatory factors. Risk factors decrease nitric oxide bioavailability and induce a proinflammatory endothelial phenotype that promotes atherosclerosis. 1,2 In human subjects, endothelial dysfunction is associated with risk factors, [3][4][5] correlates with disease progression, 6 and predicts cardiovascular events. [7][8][9][10][11][12][13] Risk reduction therapies improve endothelial function, and failure of the endothelium to respond is associated with higher risk. 14 Thus, there is strong clinical evidence that endothelial dysfunction contributes to the pathogenesis of cardiovascular disease.In the past several years, experimental and clinical studies have provided new information about the mechanisms and clinical relevance of specific aspects of endothelial function. The purpose of this review is to summarize recent articles from Circulation that have advanced this field. Mechanisms of Endothelial Dysfunction: Experimental ModelsLoss of nitric oxide bioavailability (decreased synthesis or increased degradation) is a key manifestation of endothelial dysfunction that contributes to the pathogenesis and clinical expression of atherosclerosis. Endogenous inhibitors of endothelial nitric oxide synthase (eNOS), including asymmetrical dimethyl arginine, are elevated, and contribute to endothelial dysfunction in diabetes mellitus, renal failure, and other pathological states. 15 Asymmetrical dimethyl arginine is metabolized by dimethylarginine dimethylaminohydrolase-1 (DDAH1), and using an endothelium-specific knockout mouse model, Hu and colleagues 16 demonstrated that endothelial function is importantly regulated by endothelial DDAH1. Interestingly, the DDAH1-deficient mice were hypertensive, suggesting that the vascular endothelium is involved in blood pressure regulation. Consistent with this idea, smooth muscle cell-specific deletion of guanylyl cyclase, which is the primary target of nitric oxide, 17 is also sufficient to produce hypertension in a mouse model. 18 It is well recognized that the incidence of cardiovascular events varies by time of day and the season of the year, 19 -21 and there is growing interest in the genes that regulate circadian rhythms. 22 A recent study suggests that such genes influence vascular function. Anea and colleagues 23 observed that genetic deletion of Bmal1 and Clock in mice impaired vasodilation and eNOS signaling and induced pathological arterial remodeling responses to low blood flow. Deletion of these clock genes also increased expression of prothrombotic factors by the endothelium. These results might be relevant to circadian patterns of cardiovascular events. They also raise the possibility that disruption of the biological clock in clinical situations such as sleep deprivation or jet lag might promote cardiovascular disease. 22 Another potential mechanism of endothelial dysfunction is alteration of the signaling mechanisms involved in ...

Coronary Microvascular Dysfunction Induced by Primary Hyperparathyroidism is Restored After Parathyroidectomy

“…NO is not only a major vasodilatory molecule but also the principal physiological antiatherosclerotic mediator because of its antiinflammatory, antiproliferative, immune-modulatory properties. 36 Thus, compromised NO bioavailability might be a major determinant of the impaired coronary microvascular dysfunction we observed and, on a broader perspective, a crucial factor explaining the higher risk for cardiovascular morbidity associated with PTH disturbances. In particular, PTH controls the expression and activity of endothelial NO synthase through protein kinase C (PKC) and A pathways.…”

Short-term Physical Inactivity Impairs Vascular Function

“…32,33 Dysfunctional endothelium has been recognized as an initial step in the development of atherosclerosis. 16,30 In a recent meta-analysis, Inaba et al found that a 1% decline in FMD was associated with an 8% increased risk of future cardiovascular events, highlighting the utility of this tool for cardiovascular risk prediction. 34 Our results demonstrate that when young and healthy subjects were inactive for only 5 days, FMD declined by an average 2% in both the brachial and femoral arteries.…”

“…12 Brachial artery flow-mediated dilatation (FMD) and arterial stiffness measured by arterial tonometry are used to assess vascular function and when they are impaired, they have been independently associated with increased cardiovascular risk. [13][14][15][16] The effects of a short exposure to sedentarism on vascular function are poorly understood. Furthermore, an inflammatory response is implicated in the setting of vascular dysfunction and injury.…”

The Essential Autophagy Gene ATG7 Modulates Organ Fibrosis via Regulation of Endothelial-to-Mesenchymal Transition

“…It provides a protective barrier between all tissues and the circulating blood and functions as a selective sieve to facilitate bidirectional passage of macromolecules and gases that facilitates vascular homeostasis (1,2). ECs, however, serve additional roles among which is the transition of ECs into mesenchymal cells (3).…”