Hypertension-induced venous valve remodeling.
BACKGROUND
In human beings, chronic venous insufficiency is linked to venous hypertension. This in turn is associated with venous valve incompetence. This study was designed to test the hypothesis that venous hypertension serves to initiate a process that results in the venous valve and venous wall damage observed in venous insufficiency. Material and methods Acute venous hypertension was produced by creation of an arteriovenous (AV) fistula between the femoral artery and vein in Wistar rats. At specified intervals pressure in the veins was recorded. The proximal valve containing saphenous vein was exposed, and reflux was measured from reverse blood flow through the first proximal valve. The vein was excised, valve parameters were measured, a portion was taken for morphologic investigation, and the remaining specimen was frozen in liquid nitrogen for investigation of leukocyte infiltration, expression of adhesion molecules, matrix metalloproteinase (MMP) levels, and apoptotic markers. Contralateral nonpressurized saphenous veins were used as control specimens.


RESULTS
The saphenous and femoral veins were immediately distended by pulsatile blood flow from the arterial system. Pressure was significantly increased from 11 +/- 2 mm Hg to 94 +/- 9 mm Hg. At 2 days no reflux was detected in the saphenous veins. At 1 week, one of four rats exhibited reflux; at 2 weeks, two of four rats had reflux; and at 3 weeks, three of four rats showed reflux. Contralateral saphenous veins were uniformly competent. Compared with control specimens, the veins were dilated; leaflet length and leaflet width were significantly reduced. Granulocytes, monocytes, and macrophages were identified in all regions of the vein wall, and the number was increased by the presence of the AV fistula. The number of T-lymphocytes was increased, and B-lymphocytes were present. P-selectin was upregulated in the saphenous vein walls, as was intercellular adhesion molecules. MMP-2 and MMP-9 expression in the veins was not enhanced. In the nuclear factor kappabeta family, Ikappabeta was not increased in any hypertensive veins. The number of apoptotic cells in the vein wall was increased in the presence of the AV fistula.


CONCLUSIONS
This study indicates that acute venous hypertension is accompanied by significant venous distention and some valve damage as early as 3 weeks after fistula creation. There is development of inflammatory markers, with leukocyte infiltration and increased adhesion molecule expression. We could not detect significant enhancement of MMP levels or nuclear transcription factors. It is uncertain whether this lack of evidence may be partially due to enhanced apoptosis in venous valves and vein walls. A detailed definition of the inflammatory reaction produced by venous hypertension should be the subject of further study. Clinical relevance Saphenous vein valves when observed at the time of vein stripping show deformities of shortening, scarring, and tearing. The current model of induced venous hypertension demonstrates early venous valve changes similar to those observed in human beings and links them to a venous hypertension-induced inflammatory reaction. Thus the model could be useful in pharmacologic testing to prevent or treat venous insufficiency and for defining the fundamental mechanisms that cause varicose veins.
Takase
Shinya
S
Department of Bioengineering, The Whitaker Institute of Biomedical Engineering, School of Medicine, University of California-San Diego, La Jolla, CA 92037, USA.
Pascarella
Luigi
L
Bergan
John J
JJ
Schmid-Schönbein
Geert W
GW
D000818:Animals; D001164:Arteriovenous Fistula / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D001783:Blood Flow Velocity / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology; D005268:Femoral Vein / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology*; D006973:Hypertension / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008955:Models, Cardiovascular; D019007:P-Selectin / Q000378:metabolism; D011673:Pulsatile Flow / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012501:Saphenous Vein / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation / Q000502:physiology; D014689:Venous Insufficiency / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology
D018836:Inflammation Mediators; D019007:P-Selectin