And Molecular Adhesion Mechanisms

The modern developments of the pathophysiological basis of the skin changes in CVD can perhaps be traced back to the simple observation that leukocytes have quite different biomechanical properties than the red cells. Even though they are clearly in the minority, they contribute to many microvascular events.46,47 One of them is local accumulation in the microcirculation and thus it is highly significant that blood returning from feet that have been passively dependent for 40 to 60 minutes is relatively depleted of leukocytes, especially in patients with CVD.48-50 Leukocytes are easily trapped in the microcirculation due to their stiff cyto-plasmic properties and their ability to express membrane adhesion molecules, further enhanced by the fact that these properties are changed dramatically after activation.51 This subtle mechanism suggests that leukocytes accumulate in the lower extremity under conditions of high venous pressure. It is possible that the accumulation in microvessels is due to the fact that the cells are already activated in the central circulation,6,52 which means that they may be stimulated in the circulation by a mechanism that could be located outside of the venous network of the lower extremities. Alternatively leukocytes become entrapped in the skin microcirculation by adhesion to the endothelium, which is activated by a local process not necessarily dependent on the same mechanisms that causes leukocyte activation. The leukocyte adhesion is to the membrane of the endothelium of small vessels, especially capillaries and post-capillary venules. The accumulated leukocytes became activated and led to the suggestion that an inflammatory reaction is important in provoking skin changes in CVD. Numerous recent studies have added weight to that suggestion.53-55 Most interesting in this respect are the observations by Coleridge-Smith and his colleagues, showing degranulation of the leukocytes with an increase of neutrophil elastase and lactoferrin, markers of neutrophil activation, in patients under transient conditions of venous hypertension and with chronic venous insufficiency.56-58 These enzymes may be effective activators of other proenzymes, such as MMPs. The circulating mononuclear cells of patients with CVD also have reduced degree of proliferation in response to a mito-genic challenge (staphylococcal enterotoxins) and thus a reduced capacity for wound healing.59

Skin biopsies from CVD limbs show elevated numbers of macrophages, T-lymphocytes, and mast cells.60,61 This is the same pattern as observed in both acute62,63 and chronic64 experimental rat models of venous hypertension, with elevated levels of tissue leukocytes in skin samples from affected limbs, but not from sham-operated controls.

The molecular mechanisms involved in leukocyte adhesion and activation in CVD patients are now beginning to be elucidated. For example, transient binding of L-selectin on the leucocyte surface to E-selectin on endothelial cells is involved in leukocyte "rolling" along the endothelial surface. However, when leukocytes are activated they shed L-selectin into the plasma and express molecules of the integrin family, including CD11b that binds to intercellular adhesion molecule-1 (ICAM-1). Integrin binding promotes firm adhesion of leukocytes, the starting point for their migration out of the vasculature and degranulation.

The evidence in CVD suggests that a variety of membrane adhesion molecules on endothelial cells and leukocytes (ICAM-1, vascular cell adhesion molecule-1, LFA-1, VLA-4, Mac 1, and others) appear to facilitate the adhesion and stimulate projection of pseudopodia as a requirement for transmigration of the leukocyte into the venous wall.65-68 The leukocyte infiltration of the venous parenchyma is accompanied by remodeling of the extracellular matrix, a process that is ultimately responsible for the destruction of the venous valves.

At the same time, plasma levels of soluble L-selectin increase, reflecting the shedding of these molecules from leukocyte membranes during leukocyte-endothelial adhe-sion.69 Similarly, basal plasma levels of the adhesion molecules ICAM-1, endothelial leukocyte adhesion molecule-1 (ELAM-1), and vascular cell adhesion molecule-1 (VCAM-1) are higher in CVD patients than controls and increased significantly in response to venous hypertension provoked by standing.67

In addition to local factors operating in relation to venous hypertension, CVD patients have a tendency for systemi-cally elevated leukocyte adhesion. Plasma obtained from CVD patients induced higher degrees of activation (assessed by oxygen-free radical production and pseudopod formation) in healthy, naive granulocytes than did plasma taken from normal subjects.6 The nature of the plasma factor responsible is presently unknown.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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