Sex-related decrease in [Ca2+]i signaling and Ca2+-dependent contraction in inferior vena cava of female rat

Abstract

Sex differences in the incidence of varicose veins have been suggested; however, the venous mechanisms involved are unclear. We hypothesized sex-related differences in venous function and underlying distinctions in intracellular free calcium, [Ca2+]i, signaling and Ca2+-dependent mechanisms of venous contraction. Circular segments of inferior vena cava (IVC) from male and female Sprague-Dawley rats were suspended between two hooks, labeled with fura-2, and placed in a cuvet inside a spectrofluorometer for simultaneous measurement of isometric contraction and the 340/380 fluorescence ratio (indicative of [Ca2+]i). In male IVC, phenylephrine (PHE; 10−5 M) caused significant increase in contraction and [Ca2+]i. In female IVC, PHE-induced contraction was significantly reduced, but [Ca2+]i did not differ significantly from males. Membrane depolarization by KCl (96 mM), which stimulates Ca2+ influx, caused parallel increases in contraction and [Ca2+]i in male IVC, and the KCl-induced contraction was significantly reduced in parallel with [Ca2+]i in female IVC. In male IVC stimulated with 0 Ca2+ KCl solution, the addition of increasing concentrations of extracellular Ca2+ ([Ca2+]e) (0.1, 0.3, 0.6, 1, and 2.5 mM) caused stepwise increases in contraction and [Ca2+]i, and both the KCl-induced [Ca2+]e-contraction curve and the [Ca2+]e-[Ca2+]i curve were reduced in female IVC, suggesting reduced Ca2+ entry via voltage-gated channels. The PHE-induced [Ca2+]e-contraction curve was significantly reduced in females, but the [Ca2+]e-[Ca2+]i curve was similar in female and male IVC, suggesting the involvement of other mechanisms in addition to Ca2+ entry. The [Ca2+]e-contraction and [Ca2+]e-[Ca2+]i curves were used to construct the [Ca2+]i-contraction relationship. The KCl-induced [Ca2+]i-contraction relationship was superimposed in male and female IVC. In contrast, the PHE-induced [Ca2+]i-contraction relationship was reduced and located to the right in female compared with male IVC, suggesting reduced [Ca2+]i sensitivity of the venous contractile myofilaments. The reduced contraction, [Ca2+]i, and [Ca2+]i sensitivity in female veins render them more prone to dilation. These sex-specific reductions in venous function, if they also occur in human veins, may play a role in the greater incidence of varicose veins in females.