Abnormal Endothelial Function Research Articles

Abnormal endothelial cell function of resistance arteries from women with preeclampsia

There is substantial indirect evidence that the vascular endothelium may be dysfunctional in preeclampsia and that reduced production of endothelial-derived vasodilators may account for the increased vascular resistance and enhanced pressor sensitivity characteristic of this disorder. In this study we directly investigated endothelial function by examining acetylcholine-mediated relaxation in small arteries dissected from the subcutaneous fat layer examined at the time of cesarean section. By means of a small vessel myograph we measured tension in resistance arteries of normal pregnant women (n = 12) and women with preeclampsia (n = 12) and assessed the contributions of vasodilatory prostanoids and endothelium-derived relaxing factor to endothelium-dependent relaxation, as elicited by acetylcholine, 1 nmol/L to 10 mumol/L, after precontraction with 3 mumol/L norepinephrine. Endothelium-dependent relaxation was impaired in arteries of women with preeclampsia compared with arteries from normotensive pregnant women. Endothelium-independent relaxation as assessed by sodium nitroprusside was not altered in the arteries from preeclamptic women. This study provides direct evidence of abnormal endothelial function in preeclampsia. No deficiency in endothelium-independent relaxation could be detected.

Renin-angiotensin system components and endothelial proteins as markers of diabetic microvascular disease.

Endothelial cell damage, which is associated with local thrombin formation and inflammation, can lead to the release of endothelium-synthesized factors into plasma, such as vWFAg, TM, ACE and ET-1. These markers of endothelial damage are increased in some patients with diabetes mellitus, but the differences with normal are often small and not closely correlated with the severity of microvascular disease, as judged from the degree of albuminuria and the severity of retinopathy. Prorenin, which may also be related to abnormal endothelial cell function or endothelial damage, is elevated in many patients with diabetes, both type I and II, and its level is more closely correlated with the severity of microvascular disease. It is already elevated at an early stage. Further studies will reveal whether, in diabetes, an increased plasma prorenin is a reliable predictor of progressive microvascular disease. It is even conceivable that prorenin is not only a marker of diabetic microvascular disease but also has a role in its pathogenesis, via local proteolytic or non-proteolytic prorenin activation.

Southwestern Internal Medicine Conference: The Endothelium—A Key Regulator of Vascular Tone

Emerging evidence suggests the endothelium produces several substances capable of locally regulating organ blood flow. Vasoactive prostaglandins, endothelium-derived relaxing factor, and endothelin are examples of these vasoactive substances. Abnormalities of endothelial function may contribute to the pathogenesis of disease in several circumstances, including hypertension, diabetes, and septicemia. Evidence for the endothelium as a regulator of regional perfusion and several of the endothelium-derived substances and their potential role in disease are reviewed.

Biology of the impaired endothelium

The endothelium is a regulatory organ that mediates hemostasis, contractility, cellular proliferation, and inflammatory mechanisms in the vessel wall. Injury to the endothelium from hypertension, smoking, hyperlipidemia, and diabetes mellitus disrupts normal regulatory properties and results in abnormal endothelial cell function. Clinically, endothelial cell dysfunction can be manifested as vasospasm, thrombus formation, atherosclerosis, or restenosis. The normal hemostatic properties of the endothelium include the maintenance of a nonadhesive luminal surface, antithrombotic properties, anticoagulant properties, and fibrinolytic properties. The endothelial cell regulates smooth muscle cell contractility by the production of relaxing and constricting factors in response to physiologic stimuli. Endothelial cell injury is also an initial event in the development of atherosclerosis and restenosis by facilitating platelet adhesion and aggregation and by signaling the release of mitogens from platelets, macrophages, and endothelial cells, which stimulate smooth muscle cell proliferation. In addition, endothelial cells undergo morphologic and functional alterations in response to cytokine signals, which may contribute to the pathogenesis of vasculitis and atherosclerosis. In sum, the normal endothelium performs many regulatory functions which become altered when the endothelium is injured.

Coronary flow reserve

The ability of the coronary circulation to autoregulate is essential for the heart to respond to metabolic demands. Several alterations in function may limit maximal coronary perfusion including atherosclerosis, structural abnormalities of small coronary vessels, extravascular compressive forces, thrombosis, abnormal endothelial regulatory function, and the effect of abnormal myocardium on the coronary circulation. Coronary flow reserve is a unifying concept that examines the limitation in myocardial perfusion that certain disease states impose. At present, even with state-of-the-art technology, the measurement of coronary flow reserve is difficult in routine clinical situations. As the ability to measure regional myocardial perfusion improves, coronary flow reserve may gain more widespread clinical use with perhaps as yet undiscovered therapeutic implications.

Hypothesis: Inhibition of endothelium-derived relaxing factor by haemoglobin in the pathogenesis of pre-eclampsia

Although the aetiology of pre-eclampsia is unknown, haemodynamic studies suggest that many of the clinical findings may be explained by a generalised vasoconstrictive disorder and abnormal endothelial cell function. Vasoconstriction may be attributed to the increased concentrations of haemoglobin found in pre-eclampsia compared with normal pregnancy. Free haemoglobin may be derived from haemolysis and placental haemorrhage and, at concentrations known to be present in pre-eclampsia, vasodilatation mediated by endothelium-derived relaxing factor is inhibited. Infusion of oxyhaemoglobin into human coronary arteries inhibits acetylcholine-induced vasodilatation. We suggest that an increased free haemoglobin concentration is the cause of vasoconstriction in pre-eclampsia.

Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis.

The endothelium plays a critical role in the control of vasomotor tone by the release of vasoactive substances. Because endothelial injury or dysfunction is considered important very early in atherogenesis, we hypothesized that abnormal endothelial function precedes the angiographic detection of coronary atherosclerosis in the human coronary circulation. The coronary vasomotor responses to three different endothelium-mediated stimuli (intracoronary infusion of acetylcholine 10(-8) to 10(-6) M, increase in blood flow to induce flow-dependent dilation, and sympathetic stimulation by cold pressor testing) were assessed by quantitative angiography and subselective intracoronary Doppler flow velocity measurements within the left anterior descending coronary artery in 38 patients. All three stimuli elicited epicardial artery dilation in all 11 patients with smooth coronary arteries and absence of risk factors for coronary artery disease (group 1). All nine patients with smooth coronary arteries but with hypercholesterolemia (group 2) demonstrated a selective impairment in endothelial function with vasoconstriction (35 +/- 12.7% decrease in mean luminal area) in response to acetylcholine but showed a preserved flow-dependent dilation (15.5 +/- 4.4% increase in mean luminal area) and vasodilation in response to cold pressor testing (14.2 +/- 4.6% increase in mean luminal area). In all nine patients with an angiographically defined smooth coronary artery segment but with evidence of atherosclerosis elsewhere in the coronary system (group 3), both acetylcholine and cold pressor testing induced vasoconstriction (26.2 +/- 8.7% and 18.7 +/- 7.9% decrease in mean luminal area, respectively), whereas flow-dependent dilation was preserved (20.4 +/- 8.7% increase in mean luminal area). In the nine patients with angiographic evidence of wall irregularities (group 4), flow-dependent dilation was also abolished and vasoconstriction occurred in response to acetylcholine and cold pressor testing (34.5 +/- 10.7% and 19.9 +/- 6.3% decrease in mean luminal area, respectively). All coronary artery segments dilated in response to nitroglycerin, suggesting preserved function of vascular smooth muscle. Despite similar reductions in coronary vascular resistance in response to the smooth muscle relaxant papaverin, patients with hypercholesterolemia demonstrated a selective impairment of vasodilation of the resistance vasculature in response to acetylcholine (p less than 0.05 versus groups 1, 3, and 4). Thus, there is a progressive impairment of endothelial vasoactive functioning in coronary arteries of patients with different early stages of atherosclerosis, beginning with a selective endothelial dysfunction in angiographically defined normal arteries in patients with hypercholesterolemia and progressively worsening to a complete loss of endothelium-mediated vasodilation in angiographically defined atherosclerotic coronary arteries.(ABSTRACT TRUNCATED AT 400 WORDS)

Hypothesis: inhibition of endothelium-derived relaxing factor by haemoglobin in the pathogenesis of pre-eclampsia

Although the aetiology of pre-eclampsia is unknown, haemodynamic studies suggest that many of the clinical findings may be explained by a generalised vasoconstrictive disorder and abnormal endothelial cell function. Vasoconstriction may be attributed to the increased concentrations of haemoglobin found in pre-eclampsia compared with normal pregnancy. Free haemoglobin may be derived from haemolysis and placental haemorrhage and, at concentrations known to be present in pre-eclampsia, vasodilatation mediated by endothelium-derived relaxing factor is inhibited. Infusion of oxyhaemoglobin into human coronary arteries inhibits acetylcholine-induced vasodilatation. We suggest that an increased free haemoglobin concentration is the cause of vasoconstriction in pre-eclampsia.

Photochemically induced cerebral infarction. I. Early microvascular alterations.

Cerebral ischemia leading to infarction was produced in rats by intravascular thrombosis induced by a photochemical reaction between systemically injected rose bengal and green light (560 nm) transmitted through the intact skull for a 2-min period. At 2 or 15 min following photochemical sensitization, animals were perfusion-fixed for scanning (SEM) and transmission (TEM) electron microscopic analyses of the cerebral vasculature. At 2 minutes, ultrastructural examination of cortical regions destined to undergo infarction revealed numerous platelet aggregates within both pial and intraparenchymal vessels. Platelets close to the endothelial walls were routinely degranulated with pseudopodia. Endothelial cells were frequently swollen and contained dilated mitochondria and granular endoplasmic reticulum. The endothelial luminal membrane structure was shown by high-power TEM to be focally damaged. If brain temperature was reduced by 4 degrees C during the photochemical sensitization period, the platelet response was inhibited without interfering with other ultrastructural changes. These results are consistent with the hypothesis that photochemically induced endothelial alterations stimulate platelet activation and implicate abnormal endothelial function as a primary event in the pathogenesis of photochemically induced cerebral infarction.

Do Platelets Have Anything To Do With Diabetic Microvascular Disease?

It has been postulated that abnormal platelet and endothelial function may contribute to microangiopathy in diabetes mellitus. If this proposal is correct, alterations in platelet and endothelial function should be found before the appearance of vascular disease in insulin-dependent patients and in animal models of diabetes mellitus. This appears to be the case for the following: platelet aggregation, increased platelet production of the proaggregatory prostaglandin metabolite thromboxane, decreased endothelial production of the antiaggregatory prostaglandin prostacyclin, and decreased platelet survival. Insulin therapy will return some of these findings to normal. Platelet-plasma interactions that promote platelet aggregation and increased plasma levels of the platelet-specific protein beta-thromboglobulin have been reported in insulin-dependent diabetic patients who have not manifested vascular complications as well as in those with vascular complications. It has now been demonstrated in animal models that platelet microthrombi are found in small retinal vessels after months of experimental diabetes. Collectively, these findings demonstrate that alterations in platelet and endothelial function that favor thrombosis occur early in the diabetic state and may contribute to microvascular disease. There are several ongoing studies of antiplatelet agents in diabetic vascular disease that will provide clinical evidence bearing on the major postulate. Until these and other studies are completed, the platelet-endothelial story remains an attractive hypothesis in the genesis of diabetic microvascular disease.

The ultrastructure of Descemet's membrane. III. Fuchs' dystrophy.

The ultrastructure of Descemet's membrane was studied by transmission electron microscopy in corneal buttons removed from 11 phakic eyes with Fuchs' dystrophy. Abnormalities in Descemet's membrane consistent with abnormal endothelial function early in life (prior to age 20 years) were present in all corneas. Thus, despite the relatively late clinical onset of Fuch's dystrophy, endothelial abnormalities are present quite early in life in this disease. An abnormal fibrillar layer was thicker in those corneas with greater stromal and epithelial edema, possibly indicating that this layer is formed mainly during periods of endothelial decompensation.

The Corneal Endothelium: Normal and Pathologic Structure and Function

A summary of normal and abnormal endothelial structure and function is presented. Endothelium originates from neural crest and it elaborates a banded basement membrane in utero. It is involved in mesenchymal dysgenesis of the anterior segment, like the central defect of Peters' anomaly. Cytoplasmic organelles include mitochondria that provide energy for the metabolic pump, rough endoplasmic reticulum that participate in secretion of extracellular matrix, and a terminal web that may participate in cell migration. The endothelium's main function is to control corneal hydration and nutrition with a leaky barrier formed by the apical gap and macula occludens junctions that keep some water out of the stroma but allow nutrients to pass, and with an ATPase-dependent metabolic pump that is located in the lateral plasma membranes. Endothelial wound healing involves flattening and enlargement of cells to maintain an intact monolayer as well as production of abnormal collagenous material posterior to Descemet's membrane. HLA antigens located in the plasma membrane may participate in corneal endothelial graft rejection. Clinical assessment of the endothelium involves three modalities: specular microscopy to study endothelial morphology, fluorophotometry to measure barrier function, and pachymetry to measure corneal thickness.