Under basal conditions, the endothelium continuously releases endothelium-derived relaxing factors (EDRFs) in response either to neurotransmitters such as acetylcholine or bradykinin, or to physical stimulation such as an increase in cardiac output reflecting flow-dependent endothelium-mediated vasodilatation. The most important EDRF is nitric oxide (NO), which modulates the contractile behavior of underlying vascular smooth muscle, constantly counteracting vasoconstrictor substances such as norepinephrine, angiotensin II, and endothelins. However, under physiological conditions, the shear stress of circulating blood is the most important stimulus to endothelium-dependent vasodilatation and it contributes to regional flow-induced vasodilatation during exercise.
NO is the end product of NO synthase (NOS), the enzyme that catalyzes the conversion of L-arginine to NO and L-citrulline. Two NOS isoenzymes have been identified in endothelium. The more important is endothelial constitutive NOS (ecNOS), which requires the presence of calcium, calmodulin, reduced P-nicotinamide adenine dinucleotide phosphate (NADPH), or other electron donors as cofactors. It is a highly regulated system, closely linked to the control of local vasomotor tone. Endothelium can also express a second isoenzyme, inducible NOS (iNOS), whose activity does not require calcium or calmodulin and which, once expressed, produces large amounts of NO in an unregulated fashion. iNOS is found predominantly in activated macrophages in response to cytokine activation, which induces cytotoxic amounts of NO.
Once released, NO induces vasorelaxation in conduit arteries, resistance arterioles, and veins by activating the soluble fraction of guanvlate cyclase in vascular smooth muscle. Endothelial synthesis of NO is induced by hormonal stimuli including acetylcholine, bradykinin, and serotonin. These agents act via the receptor-mediated activation of ecNOS and can be utilized clinically to quantify endothelial function.
Impaired endothelial response in heart failure
There is experimental and clinical evidence that the endothelial response to acetylcholine is significantly decreased in heart failure, resulting in impaired vasodilatation. Several mechanisms are thought to be involved:
Reduced cardiac output, hence decreased peripheral blood flow, and shear stress
These changes decrease NO synthesis, causing down-regulation of ecNOS and increased synthesis of endothelin-1. The effect of chronically decreased shear stress is to decondition endothelial function. This can be reversed by physical training, which improves exercise performance in heart failure patients due, at least in part, to the increased flow-induced, endothelium-dependent vasodilatation in the skeletal muscle circulation.
In addition to its acute effects on vascular smooth muscle tone, NO mediates changes in blood vessel structure in response to chronic reductions in hemodynamic stress. This process, termed vascular remodeling, involves rearrangement of the components of the vessel wall, including endothelial and smooth muscle cells and the collagen matrix. NO inhibits vascular smooth muscle cell mitogenesis and proliferation by a cyclic guanosine 3,5′-monophosphate (cGMP)-dependent mechanism. At the same time, endothelin-1 elevates proto-oncogene c-fos and c-myc mRNA levels, promotes endothelial and smooth muscle cell growth, and enhances mitogenesis. Vascular remodeling in heart failure is favored by neurohumoral activation, with angiotensin II and norepinephrine causing hyperplasia and hypertrophy of vascular smooth muscle cells.
Increased norepinephrine and angiotensin II levels
These neurohormones may decrease ecNOS activity either directly or indirectly by interacting with endothelin-1. Angiotensin II is a direct vasoconstrictor, acting through several specific receptors expressed in smooth muscle cells. By stimulating NADH/NADPH oxidase systems in smooth muscle cells, angiotensin II enhances the production of the superoxide anions that inactivate endothelium-derived NO. Angiotensin-con-verting enzyme (ACE) also has an indirect effect on ecNOS and NO production. Being identical to kininase
II, ACE inactivates bradykinin, which enhances ecNOS activity and NO release. For this reason, ACE inhibition has become a mandatory therapy in heart failure.
Elevated levels of tumor necrosis factor-a (TNFa) TNF-a is a macrophage-derived cytokine that has a dual effect on the biosynthesis of NO. It inhibits the expression of ecNOS, but induces the expression of iNOS, resulting in the unregulated production of large and cytotoxic amounts of NO. TNF-a may also cause endothelial dysfunction by increasing the production of oxygen free radicals that, in turn, destroy the NO produced by the endothelium. In addition, TNF-a triggers apoptosis in endothelial cells by causing oxidative stress.
Decreased shear stress, increased renin-angiotensin system activity, and increased TNF-a levels can all promote endothelial dysfunction. Apoptosis and increased endothelin-1 synthesis can also damage the endothelium. Endothelial dysfunction may further increase vasomotor tone and vascular remodeling in heart failure.
pathophysiology; endothelial dysfunction; EDRF; neurohumoral factor; vascular remodeling
How does endothelial dysfunction affect heart failure? Photo Gallery
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