Evidence for unmyelinated C fibres and inflammatory cells in human varicose saphenous vein.

The physiopathology of venous symptoms, such as pain, leg heaviness or swelling sensations, in chronic venous disease (CVD) remains unclear. Localized release of proinflammatory mediators appears to play a key role but the presence of nociceptors sensitive to inflammatory mediators, such as unmyelinated C fibres, needs to be demonstrated. The present study included 10 patients with documented CVD who underwent surgery for saphenectomy. For each patient, five segments of the great saphenous vein were immunostained with anti-S100 protein and anti-CD45 to identify nerve fibres and inflammatory cells, respectively. Light microscopy was completed by electron microscopy. In all patients, S100 immunopositive nerve fibres and CD45 immunopositive cells were observed. Under an electron microscope, advanced signs of wall remodelling were systematically observed. The density of nerve fibres was low and variable from one sample to another. Unmyelinated C fibres were mainly located in the external part of the media and to a lesser extent in the internal part of the adventitia. Inflammatory cells, mainly histiocytes, were scattered in the media. Mast cells were observed in three patients. In conclusion, unmyelinated C fibres and inflammatory cells are present in the varicose saphenous vein wall. Their linked roles in symptoms of CVD should be further explored.

Leukocyte involvement in the signs and symptoms of chronic venous disease. Perspectives for therapy.

Pain intensity in chronic venous disease varies with the stage in the clinical-etiologic-anatomic-pathophysiologic (CEAP) classification but also with patient perception, pain being by definition subjective. The venous hypertension responsible for the varicose veins and trophic changes in CVD has a variety of algogenic repercussions in which leukocytes play a particular role, notably through their ability to roll along the vessel wall. Shear stress, hypoxia and stasis activate the marginated leukocytes to shed L-selectin from their surface and express integrins, matrix metalloproteinase 9, elastase, lactoferrin and free radicals. Meanwhile the endothelium expresses adhesion molecules that permit slow rolling on E-selectin followed by adhesion and tissue transmigration. Vein wall and valve areas in particular attract mast cells, monocyte-macrophages and T lymphocytes, and undergo remodeling. Sympathetic sensory C and Adelta fibers, which wrap around cutaneous venules and are also present in the venous intima and media, are nociceptors sensitive to the pain mediators concentrated within leukocytes, such as mast cell bradykinin, responsible for visceral pain. Neuronal inflammation combined with wall remodeling intensifies symptoms. Yet no direct link has so far been shown between pain and mast cell mediator levels. Leukocyte adhesion is also associated with the increased capillary permeability that leads to edema. Antileukocyte therapies include postural rest and venotonics which alone or in combination with compression have been shown to unstick and inhibit leukocytes. The micronized purified flavonoid fraction (MPFF) protects vascular endothelium against hypoxia and reduces adhesion molecule expression. Unlike other antileukocyte therapies, venotonics do not cause neutropenia.

Roles of mechanical blood forces in vascular diseases. A clinical overview.

Under the influence of heart and elasticity of arteries, circulating blood constantly acts upon the layers of the vessels, covered by active endothelial cells. The shear stress appears like the most efficient mechanical factor developing a rubbing physical force, the laminar flow. But pulsating and centrifugal forces allow shear to be often unsteady. Mechanobiology investigates receptors and transduction across wall cells, showing that thousands of genes are activated in the endothelium leading to a lot of adaptable functions. Atherosclerosis is due to disturbances of laminar flow in specific areas where low shear allows white cells to adhere and migrate, permeability to increase. Coronaropathies, cerebral vascular accidents, aneurisms are so geometrically local diseases, of which lesions are subsequently enhanced by risk factors. Chronic venous insufficiency is also related to physical forces: hydrostatic and centrifugal pressures, and disruption of shear stress along the wall and around valvulae. Here also similar cells and biochemical phenomenons are the cause of wall remodelling and varicose. At the level of microcirculation the shear stress fall induces hypoxia, accumulation of white cells and hemorheological disorders in microvenulae. This leads to lesions of tissue, small vessel and ulcers. Numerous treatments in vascular diseases tend to restore flow and blood shearing. However a better understanding in the future should open new therapeutic fields and genetic approaches.