Vein Wall Anatomy Histopathology and Functional Alterations

Whatever the initiating event, several unique anatomic and biochemical abnormalities have been observed in patients with varicose veins. Normal and varicose greater saphenous veins (GSVs) are characterized by three distinct

FIGURE 9.1 Electron micrograph of normal greater saphenous vein (Mag 11,830x). Note organized structure of alternating smooth muscle cells (long arrows) with spindle-shaped contractile phenotype, interspersed by longitudinally arranged collagen bundles (short arrows).

muscle layers within their walls. The media contains an inner longitudinal and an outer circular layer, and the adventitia contains a loosely organized outer longitudinal layer.1214 In normal GSVs, these muscle layers are composed of smooth muscle cells (SMCs), which appear spindle-shaped (contractile phenotype) when examined with electron microscopy (see Figure 9.1).15 These cells lie in close proximity to each other, are in parallel arrays, and are surrounded by bundles of regularly arranged collagen fibers. In varicose veins, the orderly appearance of the muscle layers of the media is replaced by an intense and disorganized deposition of collagen.1517 Collagen deposits separate the normally closely opposed SMCs and are particularly striking in the media. SMCs appear elliptical rather than spindle-shaped, and demonstrate numerous collagen-containing vacuoles imparting a secretory phenotype (see Figure 9.2).15 What causes SMCs to dedifferentiate from a contractile to a secretory phenotype is currently unknown. Ascher et al. theorized that SMC dedifferentiation may be related to dysregulation of apoptosis.1819 These investigators reported a decrease in the proapoptotic mediators bax and PARP (Poly ADP-ribose polymerase) in the adventitia of varicose veins compared to normal veins. Although no difference in these mediators was observed in the media or intima of varicose veins, a decrease in SMC turnover was postulated as a possible cause for the increase in secretory phenotype. Increased phosphorylation of the retinoblastoma protein, an intracellular regulator of cellular proliferation and differentiation, has been observed in varicose veins, and may similarly contribute to this process.13

Vein wall remodeling has been observed consistently in histologic varicose vein specimens.121417,20 Gandhi et al. quantitatively demonstrated an increase in collagen content and a decrease in elastin content compared to normal GSVs.20

FIGURE 9.2 Electron micrograph of varicosed greater saphenous vein (Mag 4240x). Smooth muscle cells exhibit prominent vacuoles (arrows) and an elliptical appearance consistent with a secretory phenotype. Smooth muscle cells are separated by diffusely deposited collagen bundles which impart a disorganized architectural appearance to the vein wall.

FIGURE 9.2 Electron micrograph of varicosed greater saphenous vein (Mag 4240x). Smooth muscle cells exhibit prominent vacuoles (arrows) and an elliptical appearance consistent with a secretory phenotype. Smooth muscle cells are separated by diffusely deposited collagen bundles which impart a disorganized architectural appearance to the vein wall.

The net increase in the collagen/elastin ratio suggested an imbalance in connective tissue matrix regulation. As a result, several investigators have observed alterations in matrix metalloproteinase and fibrinolytic activity in varicose veins. TIMP-1 and MMP-1 protein levels are increased at the saphenofemoral junction compared to normal controls, whereas MMP-2 levels are decreased.21 No overall differences in MMP-9 protein or activity levels have been identified, however, the number of cells expressing MMP-9 by immunohistochemistry has been reported to be elevated in varicose veins compared to normal veins.22,23 There are conflicting reports regarding the role of plasmin activators and their inhibitors. Shireman et al. reported that uPA (urokinase plasminogen activator) levels are increased three to five times compared to normal controls in the media of vein specimens cultured in an organ bath system.24 No differences were noted in tPA (Tissue Plasminogen Activator) or PAI-1 (Plamin Activator Inhibitor-1) levels. However, other investigations have reported a decrease in uPA and tPA activity by enzyme zymography in varicose veins.22,25 These data suggest that the plasminogen activators may play a role in matrix metalloproteinase activation leading to vein wall fibrosis and varix formation; however, further research into the mechanisms regulating vein wall fibrosis clearly are needed.

What effect vein wall fibrosis has on venous function needs further elucidation. The contractile responses of varicose and normal GSV rings to noradrenaline, potassium chloride, endothelin, calcium ionophore A23187, angioten-sin II, and nitric oxide have been evaluated by several inves-tigators.26,27 These studies have demonstrated decreased contractility of varicose veins when stimulated by noradren-aline, endothelin, and potassium chloride. Similarly, endo-

thelium dependent and independent relaxations after A23187 or nitric oxide administration were diminished compared to normal GSVs, respectively. The mechanisms responsible for decreased varicose vein contractility appear to be receptor mediated.27,28 Utilizing Sarafotoxin S6c (selective pharmacologic inhibitor of endothelin B) and competitive inhibition receptor assays with 131I-endothelin-1, a decrease in endo-thelin B receptors have been observed in varicose veins compared to normal GSVs.28 Feedback inhibition of receptor production secondary to increased endothelin-1 is postulated to mediate the decreased receptor content in varicose vein walls. Other possible mechanisms for decreased contractility appear related to cAMP levels and the ratio of prostacyclin to thromboxane-A2.29 Cyclic-AMP is increased in varicose vein specimens compared to normal GSVs. In addition, the ratio of prostacyclin to thromboxane-A2 is increased even though absolute protein levels do not differ between normal veins and varicosities. Whether venodila-tion of varicosities is caused by diminished endothelin receptor levels and responsiveness to cAMP or by a secondary effect of varix formation is not known. However, it is clear that with the development of vein wall fibrosis, varicose veins demonstrate decreased contractile properties that probably exacerbate the developement of ambulatory venous hypertension.

How To Deal With Rosacea and Eczema

How To Deal With Rosacea and Eczema

Rosacea and Eczema are two skin conditions that are fairly commonly found throughout the world. Each of them is characterized by different features, and can be both discomfiting as well as result in undesirable appearance features. In a nutshell, theyre problems that many would want to deal with.

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