Smooth Muscle Cell Hypertrophy in Varicose Veins Is Associated with Expression of Estrogen Receptor-β

Abstract

Varicose veins are characterized by dilated and thickened vein walls. This study examined whether the changes that occur in varicose veins are associated with smooth muscle cell (SMC) hypertrophy, cellular proliferation or apoptosis. Moreover, the association between SMC hypertrophy and the expression of the estrogen receptor-β (ERβ) was investigated. Varicose veins were obtained from male patients during vascular stripping surgery (n = 11) and nonvaricose veins during coronary bypass surgery, also from male subjects (n = 12). The cellular volume of the SMC in both the longitudinal and circular layer of the vessel wall was measured using stereological methods. Apoptosis was detected using the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling) technique. SMC proliferation and ERβ expression were investigated by immunohistochemistry. Neither in the longitudinal nor in the circular layer of the varicose vein wall were signs of apoptosis or proliferation present. However, the mean cellular volume of the SMC in the circular layer of the varicose veins was strongly increased (5,291 ± 363 µm³) as compared to non-varicose veins (2,812 ± 212 µm³, p < 0.001). Moreover, ERβ expression in the circular layer of varicose veins (63 ± 4%) significantly differed from nonvaricose veins (39 ± 4%; p = 0.001). Interestingly, the SMC volume correlated with ERβ expression (r = 0.71, p < 0.001). These data show that cell death or proliferation of SMC do not, or only rarely, occur in varicose veins. However, remodeling of varicose veins can mainly be attributed to increased volumes of the SMC of the circular layer and this increase correlates with ERβ expression.

Differential Effects of 17β-Estradiol on Function and Expression of Estrogen Receptor α, Estrogen Receptor β, and GPR30 in Arteries and Veins of Patients With Atherosclerosis

“…37 Also possibly relevant for adverse effects of estrogen is the observation that high ER␤ expression in veins is associated with growth of vascular smooth muscle. 38 In the present study, we demonstrate that human arteries and veins express aromatase and 5␣-reductase type 1 but not 5␣-reductase type 2. Given that testosterone is locally converted to 17␤-estradiol by aromatase 39,40 and that aromatase deficiency accelerates atherogenesis in males, 41 it is possible that protective vascular effects of 17␤-estradiol are not restricted to females.…”

Autophagy in Vascular Disease

“…However, given that autophagy-deficient SMCs are hypertrophic (vide supra) and varicose veins develop SMC hypertrophy, 74 it is tempting to speculate that autophagy in SMCs of varicose veins might be impaired. Another observation that points to impaired autophagy in vascular disease, even though thorough evidence is lacking, is the accumulation of cytosolic ubiquitin inclusions in calcified, degenerative aortic valves.…”

Gender Differences of Cardiovascular Disease

“…36 ER␤ mRNA expression has also been shown to be upregulated after vascular balloon injury in males, 37 and remodeling of veins of male patients is associated with increased ER␤ expression. 38 These observations suggest that targets of "female" sex hormones are also of physiological importance in the vasculature of men. Thus, not only the female but also the male cardiovascular system seems to be an important source and target for estrogens.…”