Epidemiological studies have shown that cardiovascular disease (CVD) is less common in premenopausal women (Pre-MW) compared to men of the same age or post-menopausal women (Post-MW), suggesting cardiovascular benefits of estrogen. Estrogen receptors (ERs) have been identified in the vasculature, and experimental studies have demonstrated vasodilator effects of estrogen/ER on the endothelium, vascular smooth muscle (VSM) and extracellular matrix. Several natural and synthetic estrogenic preparations have been developed for relief of menopausal vasomotor symptoms. However, whether menopausal hormone therapy (MHT) is beneficial in postmenopausal CVD remains controversial. Despite reports of vascular benefits of MHT from observational and experimental studies, randomized clinical trials (RCTs), such as the Heart and Estrogen/progestin Replacement Study (HERS) and the Women's Health Initiative (WHI), have suggested that, contrary to expectations, MHT may increase the risk of CVD. These discrepancies could be due to age-related changes in sex hormone synthesis and metabolism, which would influence the effective dose of MHT and the sex hormone environment in Post-MW. Age-related changes in the vascular ER subtype, structure, expression, distribution, and post-ER signaling pathways in the endothelium and VSM, along with factors related to the design of RCTs, preexisting CVD condition, and structural changes in the blood vessels architecture have also been suggested as possible causes of MHT failure in CVD. Careful examination of these factors should help in identifying the causes of the changes in the vascular effects of estrogen with age. The sex hormone metabolic pathways, the active versus inactive estrogen metabolites, and their effects on vascular function, the mitochondria, the inflammatory process and angiogenesis should be further examined. Also, the genomic and non-genomic effects of estrogenic compounds should be viewed as integrated rather than discrete responses. The complex interactions between these factors highlight the importance of careful design of MHT RCTs, and the need of a more customized approach for each individual patient in order to enhance the vascular benefits of MHT in postmenopausal CVD.

Background Sex differences in the incidence of varicose veins have been reported, with greater incidence in premenopausal females than males. We hypothesized that the sex differences in venous function reflect reduced constriction and enhanced venous dilation in females compared with males, due to direct venous relaxation effects of estrogen on specific estrogen receptors (ER). Methods Circular segments of inferior vena cava (IVC) from male and female Sprague-Dawley rats were suspended between two wires and isometric contraction (in mg/mg tissue) to phenylephrine (PHE), angiotensin II (AngII) and 96 mM KCl was measured. To investigate sex differences in venous smooth muscle Ca2+ release from the intracellular stores and Ca2+ entry from the extracellular space, the transient PHE contraction in 0 Ca2+ Krebs was measured, then extracellular CaCl2 (0.1, 0.3, 0.6, 1, 2.5 mM) was added and the [Ca2+]e-dependent contraction was measured. To investigate sex differences in venous endothelial function, acetylcholine (Ach)-induced relaxation was measured. To test the role of specific ER, the amount of venous tissue ERs was measured using Western blots, and the venous relaxation in response to 17β-estradiol (E2, activator of most ERs), PPT (ERα agonist), DPN (ERβ agonist), and ICI 182,780 (ERα/ERβ antagonist, and GPR30 agonist) was measured in IVC segments non-treated or treated with the NO synthase (NOS) inhibitor L-NAME. Results PHE caused concentration-dependent contraction that was less in female (max 104. 2±16.2) than male IVC (172.4±20.4). AngII (10−6)-induced contraction was also less in female (81.0±11.1) than male IVC (122.5±15.0). PHE contraction in 0 Ca2+ Krebs was insignificantly less in female (4.8±1.8) than male IVC (7.2±1.7), suggesting little difference in the intracellular Ca2+ release mechanism. In contrast, the [Ca2+]e-dependent contraction was significantly reduced in female than male IVC. Also, contraction to membrane depolarization by 96 mM KCl, which stimulates Ca2+ influx, was less in female (129.7±16.7) than male IVC (319.7±30.4), supporting sex differences in Ca2+ entry. Ach relaxation was greater in female (max 80.6±4.1) than male IVC (max 48.0±6.1%), suggesting sex differences in endothelium-dependent relaxation pathway. Western blots revealed greater amount of ERα, ERβ and GPR30 in female than male IVC. ER agonists caused concentration-dependent relaxation of PHE contraction in female IVC. E2-induced relaxation (max 76.5±3.4) was > DPN (74.8±9.1) > PPT (71.4±12.5) > ICI 182,780 (67.4±7.8%), and was similar in L-NAME treated and nontreated IVC. Conclusion The reduced α-adrenergic, AngII, depolarization-induced, and [Ca2+]e-dependent venous contraction in females is consistent with sex differences in the Ca2+ entry mechanisms, possibly due to enhanced endothelium-dependent vasodilation and increased ER expression/activity in females. E2/ER-mediated venous relaxation in females is not prevented by NOS blockade, suggesting activation of an NO-independent relaxation pathway. The decreased veno...

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.