Endothelial dysfunction is recognized as the initial step in cardiovascular diseases. To date many intervention attempting to improve endothelial dysfunction have targeted one or more of the numerous risk factors that can cause endothelial damage. Interventions are targeted specially to the endothelium remain speculative, as a precise mechanism of endothelial dysfunctions are still being evaluated. Several pharmacological agents have been suggested to achieve vascular protection through mechanism that goes beyond the primary therapeutic action, for examples of the angiotensin-converting enzyme inhibitors or HMG-Co reductase inhibitors. Being changes to endothelial might result from promotion of vasorelaxation, inhibition of vasoconstriction, reduction of production of free radicals or other mechanisms that protect the endothelium from injury. Impairment of endothelial vasodilator function is established as a major contributor to cardiovascular disease and accumulating evidences indicates that the strategies for restoring the endothelial function can have important therapeutic effects.
Endothelium is a thin membrane that lines the inside of blood vessels, including the heart and releases factors that control vascular relaxation and contraction, thrombogenesis and fibrinolysis, and platelet activation and inhibition. Functional integrity of the endothelium is crucial for the maintenance of blood flow and antithrombotia capacity because endothelium releases humoral factors that control relaxation and contraction thrombogenesis and fibrinolysis, and platelet activation and inhibition. Thus it contributes to blood pressure control, blood flow and vessel patency. Stimulation of intact endothelial cells by neurotransmitters, hormones and substance derived from platelets includes nitric oxide and prostacyclins. Endothelial derived contracting factors include endothelin-1 (ET-1), thromboxane A2, prostaglandin H2 and components of rennin angiotensin system such as angiotensin ll.
Endothelial dysfunction is a physiological dysfunction of normal biochemical processes carried out by endothelial cell, the cells that line the inner surface of all blood vessels, arteries and veins. There occurs an imbalance between endothelium-derived relaxing and contracting factor. It may be the cause of consequence of vascular disease and is a hallmark of known cardiovascular risk factors. The endothelial dysfunctions precede structural vascular alterations. Due to imbalance between the relaxing and contracting factor which may relate to selective alterations due to pulse pressure and/or alterations in the endothelial cell functions in different areas of the vascular tree The endothelium is a target organ for the damaging effects of number of disease which includes hypertension, diabetes and hyperlipidemia as well as for vascular injuries and mechanical stresses.
Cardiovascular risk factors and endothelial dysfunctions
Hypercholesterolemia: Hypercholesterolemia per se, without the atherosclerotic vascular changes, inhibits endothelial dependent relaxation, which is further reduced in atherosclerosis. The major contributor is the oxidized low-density lipoprotein (oxoLDL) which impairs the activity of NOS synthase and also the production of NO is inactivated by superoxide radicals produced in endothelium. Endothelin is also activated in artherosclerotic vascular disease, which is due to increased endothelin gene expression by LDL.
Hypertension: Endothelial dysfunction in hypertension may contribute to an increase in peripheral vascular resistance (in small arteries) or to vascular complications of the disease. The high BP in most cases is associated with reduced endothelial dependent relaxation. Endothelial dysfunction is more prominent is some blood vessels than in others and appears to occur as blood pressure rises; thus endothelial dysfunction is a consequences rather than a cause of hypertension. Intrinsic to this abnormality is impaired synthesis of nitric oxide from its amino acid precursor L-arginine by the endothelium of the coronary vasculature and myocytes in hypertension. The underlying potential mechanisms including nitric oxide synthase gene defect, increased symmetrical dimethylarginine, augmented participation (i.e., autocrine, paracrine or intracrine) of the local renin-angiotensin, bradykinin-kinin or prostaglandin systems, and participation of other local peptides (e.g., endothelin). Thus, it is well known that angiotensin II and bradykinin inhibit or stimulate endothelial nitric oxide synthesis.
Diabetes: Elevated glucose levels in patients with diabetes cause endothelial dysfunction. The underlying mechanism may involve increased synthesis of endothelin and a vasoconstrictor prostaglandin may be elaborated in response to glucose and overcome the normal vasodilatory effect of NO released by endothelium. Recent studies have shown that elevated glucose levels increase expression of NO synthase and production of superoxide anion in vitro.
Menopause: Females suffer less frequently from cardiovascular diseases during their reproductive years than do their male counterparts. This tendency disappears after menopause, the natural state of estrogen deficiency. Estrogen replacement therapy potentially prevents the development of cardiovascular diseases in postmenopausal women. The vascular effects of estrogens are not completely understood. Estrogens lower plasma lipoproteins, influence the renin-angiotensin system, exert antioxidative properties, and may act as calcium-blocking agents. In addition, estrogens exert direct effects on the vessel wall, such as an increase of vascular NO production and modulation of endothelial NO synthase (eNOS [NOS III]) expression Increased NO production and the modulation of the lipid profile may in part underlie the well-recognized beneficial effects of estrogens on endothelial dysfunction, a prerequisite of artherosclerosis. However, it is currently thought that endothelial dysfunction is not based on reduced production but is evoked by a decreased bioavailability of NO. The latter is decisively influenced by the level of reactive oxygen species (ROS), such as superoxide, in the vessel wall. An increased production of superoxide putatively leads to the scavenging of NO and to the cellular damage associated with endothelial dysfunction.
Aging: The effect of aging on endothelial dependent vasodilatation of resistance of coronary artery in humans is characterized by significant decreased coronary blood flow in response to acetylcholine. Age related decrease in production or responsiveness of NO,
increases in the production or responsiveness to vasoconstricting factors, or increase degradation of NO in the blood vessel may contribute to this effect.
Smoking: vasoconstriction, platelet aggregation and increased monocyte adhesion are the effect of smoking that lead to increase risk of atherosclerosis and other cardiovascular diseases. The threshold for smoking dose and endothelial dysfunction appeared to be > 20 pack/year.
Potential interventions in endothelium dysfunction
Low-cholesterol diet: Dietary treatment restored impaired endothelium-dependent vascular relaxation. Monkeys fed a high fat diet develop hypercholesterolemia and over time, to atherosclerotic lesions similar to those in humans. The mechanism by which endothelium-dependent vascular relaxation was restored by cholesterol lowering is still undefined.
Exercise: According to a study of patients whose physical activity was limited by congestive heart failure, flow dependent dilation can be enhanced by physical training. Physically unfit is one of the risk factors for coronary heart disease.
Antioxidant supplements: Because oxidation of LDL-cholesterol contributes to endothelial dysfunction, investigators have reasoned that a diet rich in antioxidants may be protective. However, results of clinical studies have not consistently shown a benefit.
Pharmacologic strategies
Lipid-lowering agents: Cholesterol-lowering therapy has been associated with a deceased risk of ischemic coronary events even in the absence of antiographic regression of atherosclersis. Restoring coronary endothelial function may be more important to improved clinical outcome than reducing the degree of stances. Reversal of coronary endothelial dysfunction in patients with symptomatic coronary atherosclersosi predates changes in vascular structure. Treatment with lovastatin does not improve coronary artery endothelial responses to acetylcholine after 12 days, but improve epicardial coronary artery responses to acetylcholine at 5 and a half months. Reducing of LDL cholesterol alone failed to reverse endothelial dysfunction inn coronary arteries in another study.
ACE inhibitors: The role of the renin-agiotensin system in endothelial dysfunction related primarily to angiotensin II as a potent endothelium-derived contracting factor. The vasoconstrictive effect of tissue ACE in generating angiotensin II is normally balanced by the effects of NO and prostacyclin. When the endothelium is damaged or dysfunctional, however, the counter effects of theses endothelial vasodilators are lessened.
Calcium channel blockers: Treatment with calcium channel blocker inhibited atherogenesis to a partial degree in one of the animal studies with rabbits, without reducing arterial blood pressure in humans, several trials of calcium channel blockers have been concordant in sowing an effect of theses drugs in inhibiting the development of new lesions.
Estrogen replacement therapy: Low-dose estrogen replacement therapy appears to improve the endothelial function of vessels in post-menopausal women just as well as do higher standard doses of the hormone. Studies indicated that the benefit of estrogen include an improved lipid profile, although only 25-50% of the reduction in cardiovascular events can be attributed to lipid-lowering effects. The findings prompted some larger study, one of which involving 10 different European centres, will make a similar comparison between high- and low-dose estrogen therapy in women.
Strategies specifically targeted to restoration of endothelial functions may be expected to reverse or reduce the progression of vascular diseases and to normalize vascular reactivity. An improved endothelial function appears to be possible via variety of current available methods, with the novel approaches still to come. It seem reasonable to expect that future therapeutic strategies and agents will be directly targeted to this monolayer of cells that regulates vascular tone and structure. Early detection of endothelial dysfunction may be measure to guide therapy prior to the development of symptomatic cardiovascular diseases.
(The authors are with Pharmacy Group, Birla Institute of Technology and Science, Pilani, 333031. Email:anantha@bits-pilani.ac.in)