Article

The Barrier Within: Endothelial Transport of Hormones

Diabetes and Obesity Research Institute, Department of Biomedical Science, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Physiology (Impact Factor: 4.86). 08/2012; 27(4):237-47. DOI: 10.1152/physiol.00012.2012
Source: PubMed

ABSTRACT

Hormones are involved in a plethora of processes including development and growth, metabolism, mood, and immune responses. These essential functions are dependent on the ability of the hormone to access its target tissue. In the case of endocrine hormones that are transported through the blood, this often means that the endothelium must be crossed. Many studies have shown that the concentrations of hormones and nutrients in blood can be very different from those surrounding the cells on the tissue side of the blood vessel endothelium, suggesting that transport across this barrier can be rate limiting for hormone action. This transport can be regulated by altering the surface area of the blood vessel available for diffusion through to the underlying tissue or by the permeability of the endothelium. Many hormones are known to directly or indirectly affect the endothelial barrier, thus affecting their own distribution to their target tissues. Dysfunction of the endothelial barrier is found in many diseases, particularly those associated with the metabolic syndrome. The interrelatedness of hormones may help to explain why the cluster of diseases in the metabolic syndrome occur together so frequently and suggests that treating the endothelium may ameliorate defects in more than one disease. Here, we review the structure and function of the endothelium, its contribution to the function of hormones, and its involvement in disease.

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    • "Indeed, the efficiency and extent of insulin delivery to the interstitial space can be inhibited physiologically by diet [30]. The mechanism via which insulin crosses the endothelium is at least in part via the paracellular pathway and for more information on this topic readers are referred to recent excellent review articles by Kolka and Bergman [14,31]. "
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    ABSTRACT: The vascular endothelium is a dynamic structure responsible for the separation and regulated movement of biological material between circulation and interstitial fluid. Hormones and nutrients can move across the endothelium either via a transcellular or paracellular route. Transcellular endothelial transport is well understood and broadly acknowledged to play an important role in the normal and abnormal physiology of endothelial function. However, less is known about the role of the paracellular route. Although the concept of endothelial dysfunction in diabetes is now widely accepted, we suggest that alterations in paracellular transport should be studied in greater detail and incorporated into this model. In this review we provide an overview of endothelial paracellular permeability and discuss its potential importance in contributing to the development of diabetes and associated complications. Accordingly, we also contend that if better understood, altered endothelial paracellular permeability could be considered as a potential therapeutic target for diabetes.
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    ABSTRACT: Hemodynamic forces, such as pressure and flow/wall shear stress, are important determinants of acute and chronic, functional, and morphological adaptations of arterial vessels. An acute increase in intraluminal pressure is known to elicit myogenic constrictor response of arteries, and arterioles. However, when pressure increases for longer periods of time, it activates - in addition to the contractile machinery - many other intracellular signaling pathways in the vascular wall, such as oxidative enzymes and the renin-angiotensin system (RAS). These then lead to functional and eventually morphological adaptations. The other mechanical force, wall shear stress related to changes in blood flow, activates extracellular flow-sensing elements associated with the endothelium surface layer, glycocalyx, which communicate the signal to membrane-bound complexes and to eNOS and other enzymes. Acute stimulation of the endothelium by flow/shear stress leads to vasodilatation (in most tissues) due to the release of NO in addition of other vasoactive agents including prostacyclin and EDHF. In some pathological conditions, vasoconstrictor agents are produced, such as endothelin-1, angiotensin II, or thromboxane A2. Chronic presence of high flow/shear stress likely to be beneficial to control growth processes, but it could also lead to the activation of oxidative enzymes and alter receptor functions. Reactive oxygen species (ROS) produced in response to hemodynamic forces may interact directly with NO thus reducing its bioavailability. In addition, ROS can reduce the level of tetrahydrobiopterin, an essential cofactor for eNOS leading to uncoupling of the enzyme, which in turn produces ROS instead of NO. Excessive ROS production is associated with a reduced vasodilatation as observed in cardiovascular diseases. When blood pressure and/or flow increase chronically, they trigger diameter enlargement and medial hypertrophy in order to normalize tensile stresses and shear stress aiming to adapt the vasomotor function to the altered environment. Such remodeling of vascular tissues is initiated by pro-inflammatory mechanisms, in part induced by peroxynitrite and activation of vascular RAS. In addition, activation of MMPs leads to extracellular matrix remodeling, which allows morphological changes. In parallel, angiotensin II type 1 receptor stimulation and ERK1/2 activation are involved in the compensatory hypertrophy associated with the diameter enlargement. Thus, hemodynamic forces activate ROS formation and vascular RAS, both of which are necessary for functional changes and remodeling of arterial vessels. In diseased conditions (hypertension, diabetes), these events became even more complicated and lead to maladaptive remodeling impairing the appropriate regulation of tissue blood flow by vasomotor mechanisms leading to diseases of parenchymal tissues. © Springer-Verlag Berlin Heidelberg 2014. All rights are reserved.
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