Endothelium-derived relaxing factor (EDRF) is an endogenous vasodilator that endothelial cells produce and subsequently release in response to various changes in normal physiologic as well as pathophysiologic changes. EDRF causes vascular smooth muscle to relax, as it activates soluble guanylate cyclase and subsequently increases cyclic guanylate monophosphate in vascular smooth muscle. EDRF is structurally in the form of nitric oxide (NO) or a compound that contains nitrogen oxide. EDRF is formed from L-arginine by an enzyme that is dependant on calcium-calmodulin and NADPH. EDRF serves as an inhibitor of aggregation and adhesion of platelets and is a vasodilator. EDRF also serves as a second messenger for guanylyl cyclase activation and cyclic GMP production. EDRF’s function, pathophysiology, and it's clinical significance will be the subject in this review.
All vascular beds, small and large vessels contain EDRF; this is true for many species. EDRF acts directly on vascular smooth muscle to invoke endogenous vasodilation and inhibiting sympathetic vasoconstriction. It is the active particle in nitrovasodilating agents such as nitrates and nitroglycerin. EDRF functions as a second messenger for activation of guanylyl cyclase and the production of cyclic GMP for cells in cardiovascular tissue, respiratory and renal epithelium, macrophages, neurons of the cerebellum, and adrenocytes.
EDRF serves as nitric oxide that functions through activating soluble guanylyl cyclase. Endothelial cell membranes contain an enzyme called endothelial nitric oxide synthase which produces nitric oxide, which then binds to soluble guanylyl cyclase in smooth muscle cells. This binding triggers a cell signaling cascade, ultimately leading to arteriole vasodilation. This process of endogenous nitric oxide production physiologically modulates blood flow and vasomotion.
It also has antiplatelet properties by inhibiting platelet adhesion and platelet aggregation. The decrease in platelet activation directly leads to an anti-thrombotic effect. NO also has anti-inflammatory properties by intrinsic inhibition of leukocytes adhesion to the endothelium. It is this antithrombotic effect along with arteriole vasodilation that has had such a huge impact on the clinical arena.
Pathophysiologic conditions affected by EDRF dysfunction include an increase in monocyte and platelet adhesion to the endothelium, myocardial infarction, atherosclerosis, and stroke. This activity may be due to increased peripheral vascular tone caused by increased superoxide radical inactivation of NO or impaired NO synthesis. For example, the first step to the atherosclerotic process is endothelial dysfunction.
The quiescent endothelial cell in its normal state is attached to the endothelial cell surface and attached to the basement membrane. The endothelial cell has protective mechanisms against endothelial glycocalyx dysfunction and endothelial cell dysfunction. These protective mechanisms include a functional glycocalyx which coats the external surface of the plasma membrane in a composition of glycoprotein and glycolipid and several micro as well as macro physiologic responses to stress.
Type 1 endothelial activation, type 2 endothelial activation, endothelial apoptosis, and endothelial necrosis, all lead to endothelial dysfunction. Type 1 endothelial activation occurs almost immediately and does not require gene transcription or de novo protein synthesis. Type 2 endothelial activation can occur over a longer period, taking hours, days, or even months in some cases. In contrast to type 1 endothelial dysfunction, type 2 endothelial dysfunction requires gene transcription and de novo protein synthesis, thus requiring a longer period to progress. If endothelial activation is uncontrolled, type 2 endothelial activation can lead to endothelial apoptosis. Chronic endothelial activation can then lead to endothelial necrosis. This is significant in cardiorenal syndrome, where endothelial dysfunction may serve as an intersection between renal dysfunction and cardiac dysfunction.
Endothelial cell activation can lead to reversible endothelial dysfunction. In this case, target treatment aims to restore normal endothelial cell function and to stop the reversible endothelial dysfunction. However, if the reversible endothelial dysfunction progresses without treatment, it can lead to endothelial apoptosis and endothelial necrosis. Both endothelial apoptosis and necrosis lead to irreversible endothelial dysfunction. In this case, target treatment cannot restore normal endothelial cell function nor stop reversible endothelial dysfunction.
Cardiovascular disease is among the leading causes of death today. Atherosclerosis and hypertension are major risk factors for cardiovascular disease. Endothelial dysfunction also plays a crucial role in atherosclerotic disease and hypertension. Dysfunction in EDRF can lead to an increase in platelet adhesion which subsequently increases the risk of a prothrombotic state. Dysfunction in the relaxation factor also leads to paradoxical vasoconstriction. As hypertension worsens, the increased intravascular pressures may lead to further endothelial damage. Both atherosclerotic disease and hypertension put patients at risk for more life-threatening conditions such as myocardial infarction and/or stroke.
Interventions that aim to treat endothelial dysfunction, target the underlying risk factors that cause endothelial damage. For example, medications such as ACE inhibitors and calcium channel antagonists treat hypertension, and lipid-lowering agents are used for hypercholesterolemia. Lifestyle modification also plays a large role in treatment. Smoking cessation helps to decrease the possible ramifications of cigarette smoking on endothelial dysfunction, and an increase in physical activity is used to prevent endothelial dysfunction due to a sedentary lifestyle. Chronic conditions that can lead to endothelial dysfunction can also be treated, such as increasing control of abnormal metabolic conditions in diabetes mellitus and estrogen replacement therapy in menopause. Pharmacologic agents that can achieve vascular protection in addition to their primary therapeutic indications are ACE inhibitors and HMG COA reductase inhibitors. All of these interventions help induce positive changes in the endothelium due to inhibition of vasoconstriction, promotion of vasorelaxation, decreased free radical production, or other protective mechanisms against endothelial injury.
Stimulators of EDRF release include insulin and adiponectin. Chronic NO release by endothelial cells can be upregulated by dietary factors, estrogen, and exercise, and downregulated by oxidative stress, pollution, smoking, and oxidized low-density lipoproteins. NO release is also decreased with aging and in vascular diseases such as hypertension and diabetes. With impaired nitric oxide production, such as by oxidative stress, spontaneous hypertension, aging, and diabetes, this exacerbates endothelium-dependent contractions, and can contribute to decreased endothelium-dependent vasodilation in patients with essential hypertension or diabetes, as well as aging patients. Endothelin 1 can also contribute to endothelial dysfunction and vascular dysfunction. Also, under conditions of hypoxia, nitric oxide can cause unbalanced activation of soluble guanylyl cyclase such that cyclic inosine monophosphate (cIMP) production increases, instead of cGMP. This increased cIMP can then lead to contraction of underlying vascular smooth muscle, instead of relaxation.
Ischemic diseases with impaired endothelial function have impaired EDRF formation and release into the vasculature include hypercholesterolemia, atherosclerosis, hypertension-induced vascular damage, diabetes, reperfusion damage, coronary spasm, and subarachnoid hemorrhage-induced vasospasm. In these ischemic diseases, there is decreased EDRF release or hemoglobin or oxygen-derived radicals immediately inactivate the released NO before affecting the vasculature. Due to impaired EDRF release, there is an increased vasoconstrictor tone, and this is exacerbated by insufficient receptor-stimulated or mechanical NO release in large feed arteries such as coronaries. This increased vasoconstrictor tone can cause inadequate blood supply which leads to ischemic damage.
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