Microcirculation : the official journal of the Microcirculatory Society, Inc
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Increased endothelial permeability is the hallmark of inflammatory vascular edema. Inflammatory mediators that bind to heptahelical G protein-coupled receptors trigger increased endothelial permeability by increasing the intracellular Ca2+ concentration ([Ca2+]i). The rise in [Ca2+]i activates key signaling pathways that mediate cytoskeletal reorganization (through myosin-light-chain-dependent contraction) and the disassembly of VE-cadherin at the adherens junctions. ⋯ In addition, TRPC4-/- mouse-lung endothelial cells exhibited lack of actin-stress fiber formation and cell retraction in response to thrombin activation of protease-activated receptor-1 (PAR-1) in endothelial cells. The increase in lung microvascular permeability in response to PAR-1 activation was inhibited in TRPC4-/- mice. These results indicate that endothelial TRP channels such as TRPC1 and TRPC4 play an important role in signaling agonist-induced increases in endothelial permeability.
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This review evaluates (1) the regulation of water and solute transport across the endothelial barrier in terms of pore theory and the glycocalyx-junction-break model of capillary permeability; and (2) the mechanisms regulating permeability based on experiments using cultured endothelial cells and intact microvessels. ⋯ The current form of the glycocalyx-junction-break model of capillary permeability describes the selectivity of the capillary wall (pore size) in terms of the space between the fibers of a quasi-periodic matrix on the endothelial cell surface, and the area for exchange (pore number) in terms of the length and frequency of breaks in the tight junction strands. An independent test of this model in a range of mammalian microvascular beds is new experimental evidence that the colloid osmotic pressure of plasma proteins is developed across the glycocalyx, not across the whole microvessel wall. We are beginning to understand that endothelial cells may change their phenotype in response to physical and chemical stresses. Such changes in phenotype may explain changes in the regulation of endothelial barrier function in intact microvessels that have previously been exposed to injury and differences in the regulation of contractile mechanisms between endothelial cells in vivo and in vitro.
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Shock is accompanied by a severe inflammatory cascade in the microcirculation, the origin of which has been hypothesized in the past to be associated with specific mediators such as endotoxin, oxygen free radicals, nitric oxide, cytokines, and lipid products. But no intervention with clinical effectiveness has been derived from these ideas to date. The authors propose here a new hypothesis suggesting that degradative enzymes, synthesized in the pancreas as part of normal digestion, may play a central role in shock and multiorgan failure. ⋯ Digestive enzymes thereby gain access to the wall of the intestine and initiate self-digestion of submucosal extracellular matrix proteins and interstitial cells. The process leads to generation and release of a host of strong inflammatory mediators. The authors hypothesize that inhibition of pancreatic enzymes in the lumen of tile intestine can serve to attenuate formation of these inflammatory mediators in ischemic tissues following hemorrhagic shock, and consequently prevent cell and tissue injury as well as multiorgan failure.
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The microvascular dysfunction which occurs in sepsis involves all three elements of the microcirculation: arterioles, capillaries, and venules. In sepsis, the arterioles are hyporesponsive to vasoconstrictors and vasodilators. Sepsis also reduces the number of perfused capillaries, thereby impacting on oxygen diffusion to mitochondria. ⋯ In addition, PMN-endothelial adhesive interactions occur in precapillary microvessels and capillaries in organs, such as, the lung and heart. Thus, all these elements of the microcirculation are involved in the sepsis-induced inflammation. In this review we address emerging views on the mechanisms involved in the microvascular dysfunction induced by sepsis within the framework of these three basic elements of the microcirculatory unit.
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The elevated ambulatory pressure in the peripheral venous system of chronic venous insufficiency (CVI) patients manifests itself not only in the form of disturbed macrocirculation but also and particularly in microangiopathic changes. For this reason, it is closely correlated with trophic disorders of the skin and can ultimately lead to ulceration. Using microcirculation research techniques, we are able to provide clear evidence of a typical microangiopathy in chronic venous insufficiency. ⋯ These changes represent a plausible explanation for the development and to recurrency tendency of venous ulcers. The reduced expression of lymphocytic L-selectin in healthy controls during the orthostatic stress test may be an indication that the cells are activated by venous stasis. Clinically effective therapeutic measures improve the impaired microcirculation of the skin in the ankle area.