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

Abstract

Background Varicose Veins (VarV) is a common disorder of venous dilation and turtuosity with unclear mechanism. Although venous smooth muscle constitutes a significant component of the vein wall, the functional integrity and the ability of various regions of the VarV to constrict is unclear. The objective of this study was to test the hypothesis that the different degrees of venodilation in different regions of VarV reflect segmental differences in the responsiveness to receptor-dependent vasoconstrictive stimuli and/or in the post-receptor signaling mechanisms of vasoconstriction. Methods Varix segments and adjacent proximal and distal segments were obtained from patients undergoing VarV stripping. Control greater saphenous vein specimens were obtained from patients undergoing lower extremity arterial bypass and coronary artery bypass graft (CABG). Circular vein segments were equilibrated under 2 g of tension in a tissue bath, and the 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 using Western blot analysis. Results AngII 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-receptor-mediated contractile mechanisms. Western blot analysis revealed similar amount of AT1R in VarV compared to control veins. 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), that was greater in magnitude than 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 VarV (max 32.1±6.4 mg/mg tissue, pED50 4.89±0.13) as compared to 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 segments of VarV, indicating tissue viability and intact Ca2+-dependent contraction mechanisms. Conclusions Compared with control veins, different regions of VarV display reduced AngII-mediated venoconstriction, which may play a role in the progressive dilation in VarV. Post-receptor Ca2+-dependent contraction mechanisms remain functional in VarV. 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.

A comprehensive characterisation of the metabolic profile of varicose veins; implications in elaborating plausible cellular pathways for disease pathogenesis

“…The control group included great saphenous vein samples from patients undergoing lower limb bypass operations or amputations in addition to vein samples from other anatomical locations such as the neck and lower abdomen, which are subject to different biomechanical stresses than the GSV. While statins and most other cardiovascular medications have a short half-life (less than 24 hours) 24 and neither parent drugs nor their metabolites were detected in our NMR or LCMS based profiling, it is possible that the above factors confounded the presented results by pharmacological effect. It is, nonetheless, important to stress that despite these issues the varicose vein samples were consistently different from the control groups in the statistical modelling, suggesting that any variability within the non-varicose veins groups was far outweighed by the differences between the two groups.…”

Endothelium-dependent nitric oxide and hyperpolarization-mediated venous relaxation pathways in rat inferior vena cava

“…We have previously studied vein functions in circular segments of human saphenous vein and varicose veins. 50 We have shown that membrane depolarization by high 96 mM KCl solution causes significant contraction of human saphenous vein. Whether membrane hyperpolarization plays a role in human vein relaxation is unclear and should represent an important area for future investigations.…”

In-vitro Identification of Distinctive Metabolic Signatures of Intact Varicose Vein Tissue via Magic Angle Spinning Nuclear Magnetic Resonance Spectroscopy

“…However, to our knowledge, there has been no demonstration of the effect of age on metabolic profile of vein tissue so far. Statins and most of the other cardiovascular medications have a short half-life (less than 24 h) 41 and neither parent statins nor their metabolites were detected in the NMR profiles. Although this does not evade the possibility that an endogenous metabolic response to chronic use of statins might be detected, in light of the nature of the metabolic changes it seems unlikely that statins would be responsible for any of the observed differences in metabolic profile between the varicose vein and control groups.…”