Sexual dimorphism in the permeability response of coronary microvessels to adenosine

Abstract

Gender influences volume regulation via several mechanisms; whether these include microvascular exchange, especially in the heart, is not known. In response to adenosine (Ado), permeability (P(s)) to protein of coronary arterioles of female pigs decreases acutely. Whether Ado induces similar P(s) changes in arterioles from males or whether equivalent responses occur in coronary venules of either sex has not been determined. Hypotheses that 1) basal P(s) properties and 2) P(s) responses to vasoactive stimuli are sex independent were evaluated from measures of P(s) to two hydrophilic proteins, alpha-lactalbumin and porcine serum albumin (PSA), in arterioles and venules isolated from hearts of adult male and female pigs. Consistent with hypothesis 1, basal P(s) values of both microvessel types were independent of sex. Contrary to hypothesis 2, P(s) responses to Ado varied with sex, protein, and vessel type. Confirming earlier studies, Ado induced a approximately 20% decrease in P(s) to both proteins in coronary arterioles from females. In arterioles from males, Ado did not change P(s) for alpha-lactalbumin (P(s)(alpha-lactalb), 3 +/- 13%), whereas P(s) for PSA (P(s)(PSA)) decreased by 27 +/- 8% (P < 0.005). In venules from females, Ado elevated P(s)(PSA) by 44 +/- 20% (P < 0.05), whereas in those from males, Ado reduced P(s)(PSA) by 24 +/- 5% (P < 0.05). The variety of outcomes is consistent with transvascular protein and protein-carried solute flux being regulated by multiple sex-dependent mechanisms in the heart and provides evidence of differences in exchange homeostasis of males and females in health and, likely, disease.

Fig. 1

Basal coronary arteriole permeability (Ps)to α-lactalbumin and to porcine serum albumin (PSA) is shown for microvessels isolated from hearts of female and male pigs. Data are means ± SE. There is no statistical difference in Ps to either solute with sex (P = 0.36 and 0.40 for α-lactalbumin and PSA, respectively). Whether the data are combined or split by sex, permeability to α-lactalbumin is greater than that to PSA (*P < 0.05).

Fig. 2

Under basal conditions, a gradient in permeability exists between arterioles and venules isolated from male and female pig hearts. Mean Ps to PSA ($P_{\mathrm{s}}^{\mathrm{PSA}}$) is shown for arterioles and venules isolated from hearts of 52 female and 27 male pigs. Data are means ± SE and are grouped because there are no differences in Ps in either vessel type with sex. *P < 0.05.

Fig. 3

Sex- and microvessel-sensitive changes in Ps to PSA in response to adenosine (Ado, 10⁻⁵ M). The paired mean permeability response ($P_{\mathrm{s}}^{\mathrm{Ado}}∕P_{\mathrm{s}}^{\mathrm{C}}$, where C is control) to a minimum of 5 min of suffusion with Ado is shown for PSA in arterioles (left) and venules (right) isolated from hearts of female (open bars) and male (shaded bars) pigs. Data are means ± SE. *P < 0.05, significant changes in permeability from basal levels. Significant differences also exist in direction and magnitude of responses with sex (**P < 0.01) and vessel type in females (***P < 0.01).

Fig. 4

Comparison of distribution of coronary arteriolar permeabilities to PSA and α-lactalbumin before (◇) and after (◆) exposure to Ado. Data are means ± SE for arterioles isolated from female (A) and male (B) hearts, respectively. On the abscissa is Ps for the larger protein, PSA ($P_{\mathrm{s}}^{\mathrm{PSA}}$), and on the ordinate is Ps for the smaller protein, α-lactalbumin $P_{\mathrm{s}}^{\alpha \text{-lactalbumin}}$. A solid line is drawn with a slope of 1.7 indicating where the data would lie if the solutes were to cross the arteriolar wall by free diffusion (Df, free diffusion coefficient). The shaded area is where the data would be expected to fall if the arteriolar barrier contained structures that further restricted the passage of large relative to small macromolecules (ultrafiltration). SED, sedentary animals.