Imbalance between the endothelial cell‐derived contracting factors prostacyclin and angiotensin II and nitric oxide/cyclic GMP in human primary varicosis

Abstract

1 The role of the endothelium in the vasomotor control of human veins in the lower extremity is little understood. We tested the hypothesis that the production of relaxing and contracting factors is altered in endothelial cells from varicose saphenous veins which may predispose to the decreased vessel tone observed in primary varicosis. 2 We determined the intracellular accumulation of guanosine 3':5'-cyclic monophosphate cyclic GMP; a measure of nitric oxide production) and the release of endothelin and prostacyclin (measured as its stable metabolite 6-keto-prostaglandin F 1a ) from cultured cells derived from the long saphenous veins of patients with primary varicosis (Varicose saphena group, n=27) or from patients undergoing coronary artery bypass surgery (Healthy saphena group, n=22). In addition, levels of endothelin, angiotensin II, bradykinin, cyclic GMP and cyclic AMP in plasma from patients with primary varicosis and healthy volunteers (n=8 ± 11 in each group) were determined. 3 Although basal cyclic GMP levels were similar, more cyclic GMP accumulated in response to histamine (1 ± 100 mmol l 71 ) in cells from varicose saphenous veins (0.75+0.1 pmol per well) than in cells from veins without varicosis (0.27+0.05 pmol per well). Furthermore, the relaxant potency of nitroprusside (1 nmol l 71 ± 300 mmol l 71 ) in vitro was higher for varicose veins (mean EC 50 =5.9 m mol l 71 ; n=8) than healthy veins (mean EC 50 =20.0 mmol l 71 ; n=7). 4 The production of prostacyclin was signi®cantly less in cells from varicose than healthy saphenous veins (66+8.7 and 121+20.1 nmol g 71 protein), but the production of endothelin was similar in both groups. Prostacyclin (3 nmol l 71 ± 30 mmol l 71 ) consistently contracted rings of varicose saphenous vein in vitro with a mean EC 50 value of 10 ± 20 mmol l 71 (n=7); the maximum tension generated was *50% of that of a completely depolarizing solution of K + (120 mmol l 71 ). 5 In plasma from patients with varicose veins, levels of cyclic GMP were higher than in healthy controls (9.2+0.03 and 7.2+0.02 nmol l 71 ), levels of angiotensin II were lower (81+11.5 and 147+21.7 pmol l 71 ), and levels of endothelin, cyclic AMP, and bradykinin were not di erent. 6 It is concluded that endothelial cells from diseased saphenous veins secrete less constrictor mediators than cells from healthy veins and that in diseased veins the nitric oxide/cyclic GMP system is upregulated which may shift the balance of vasoactive factors towards vasodilatation and contribute to the development of primary varicosis.

Current Advances in the Pathogenesis of Varicose Veins

“…In addition, activated endothelial cells release growth factors that induce smooth muscle cell migration, proliferation and de-differentiation into the synthetic phenotype, leading to the formation of neointima [26]. Histology analysis showed that endothelial cells from varicose veins had the reduced endothelin-1 binding and endothelin-B receptor density as well as reduced production of the endothelial cell-derived contracting factors prostacyclin and angiotensin II, which may be partially responsible for the reduced vasocontractility in varicose veins [27,28]. Matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs), regulate and maintain the extracellular matrix.…”

Functional adaptation of venous smooth muscle response to vasoconstriction in proximal, distal, and varix segments of varicose veins

“…Although the reduced AngII responsiveness could be due to localized alterations in VarV, it could also be a component of a more generalized change in the renin-angiotensin system and its effects on the venous system. This is supported by reports that the renin-angiotensin system is suppressed and that the circulating levels of AngII are reduced in the plasma of patients with VarV 30. It is possible that in the presence of a decreased responsiveness to AngII, a maintained response to PHE may represent a compensatory mechanism to maintain venous tone against the increased venous pressure associated with VarV.…”

Ca2+ mobilization in saphenous vein smooth muscle cells derived from patients with primary varicosity

“…The hypothesis of a defective smooth muscle tone is supported by clinical observations and experimental studies in which varicose veins showed a reduced ability to contract in response to several vasoconstrictors including α‐adrenoceptor agonists and endothelin [9–11]. The possible role of an imbalance between endothelium‐derived contracting and relaxing factors was reported by our group [12].…”