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

BackgroundVaricose veins (VarVs) are a common disorder of venous dilation and tortuosity with unclear mechanism. The functional integrity and the ability of various regions of the VarVs to constrict is unclear. This study tested the hypothesis that the different degrees of venodilation in different VarV regions reflect segmental differences in the responsiveness to receptor-dependent vasoconstrictive stimuli and/or in the postreceptor signaling mechanisms of vasoconstriction.MethodsVarix segments and adjacent proximal and distal segments were obtained from patients undergoing VarV stripping. Control great saphenous vein specimens were obtained from patients undergoing lower extremity arterial bypass and coronary artery bypass grafting. Circular vein segments were equilibrated under 2 g of tension in a tissue bath, and changes in isometric constriction in response to angiotensin II (AngII, 10–11-10–7 M), phenylephrine (PHE, 10–9-10–4 M), and KCl (96 mM) were recorded. The amount of angiotensin type 1 receptor (AT1R) was measured in vein tissue homogenate.ResultsAngII caused concentration-dependent constriction in control vein (max 35.3 ± 9.6 mg/mg tissue, pED50 8.48 ± 0.34). AngII caused less contraction and was less potent in proximal (max 7.9 ± 2.5, pED50 6.85 ± 0.61), distal (max 5.7 ± 1.2, pED50 6.74 ± 0.68), and varix segments of VarV (max 7.2 ± 2.0, pED50 7.11 ± 0.50), suggesting reduced AT1R-mediated contractile mechanisms. VarVs and control veins had similar amounts of AT1R. α-adrenergic receptor stimulation with PHE caused concentration-dependent constriction in control veins (max 73.0 ± 13.9 mg/mg tissue, pED50 5.48 ± 0.12) exceeding that of AngII. PHE produced similar constriction and was equally potent in varix and distal segments but produced less constriction and was less potent in proximal segments of VarVs (max 32.1 ± 6.4 mg/mg tissue, pED50 4.89 ± 0.13) vs control veins. Membrane depolarization by 96 mM KCl, a receptor-independent Ca2+-dependent response, produced significant constriction in control veins and similar contractile response in proximal, distal, and varix VarV segments, indicating tissue viability and intact Ca2+-dependent contraction mechanisms.ConclusionsCompared with control veins, different regions of VarV display reduced AngII-mediated venoconstriction, which may be involved in the progressive dilation in VarVs. Postreceptor Ca2+-dependent contraction mechanisms remain functional in VarVs. The maintained α-adrenergic responses in distal and varix segments, and the reduced constriction in the upstream proximal segments, may represent a compensatory adaptation of human venous smooth muscle to facilitate venous return from the dilated varix segments of VarV.

Clinical RelevanceThe dilated and tortuous nature of varicose veins (VarVs) has been partly explained by extensive vascular tissue remodeling and extracellular matrix degradation. Venous smooth muscle apoptosis and inability to contract have also been suggested to contribute to the dilated venous state in VarVs. The present study demonstrates specific reduction in venous constriction to angiotensin II in different VarV regions. This is not due to decreased angiotensin type 1 receptor (AT1R) expression but appears to involve decreased sensitivity of AT1R-mediated contractile signaling pathways. The maintained response to phenylephrine and membrane depolarization by KCl suggests that the α-adrenergic receptor-mediated signaling pathways, the Ca2+-dependent contraction mechanisms, and the venous contractile myofilaments are still functional in the varix region of the VarV. The results highlight the importance to further explore a potential relation between changes in the renin-angiotensin system and the incidence of VarVs and also suggest that genetic manipulations or pharmacologic tools to enhance the activity of venous AT1R may represent a potential approach in the management of VarVs.