Intrinsic sex-specific differences in microvascular endothelial cell phosphodiesterases

Abstract

The importance of gonadal hormones in the regulation of vascular function has been documented. An alternate and essential contribution of the sex chromosomes to sex differences in vascular function is poorly understood. We reported previously sex differences in microvessel permeability (P(s)) responses to adenosine that were mediated by the cAMP signaling pathway (Wang J, PhD thesis, 2005; Wang J and Huxley V, Proceedings of the VIII World Congress of Microcirculation, 2007; Wang J and Huxley VH, Am J Physiol Heart Circ Physiol 291: H3094-H3105, 2006). The two cyclic nucleotides, cAMP and cGMP, central to the regulation of vascular barrier integrity, are hydrolyzed by phosphodiesterases (PDE). We hypothesized that microvascular endothelial cells (EC) would retain intrinsic and inheritable sexually dimorphic genes with respect to the PDEs modulating EC barrier function. Primary cultured microvascular EC from skeletal muscles isolated from male and female rats, respectively, were used. SRY (a sex-determining region Y gene) mRNA expression was observed exclusively in male, not female, cells. The predominant isoform among PDE1-5, present in both XY and XX EC, was PDE4. Expression mRNA levels of PDE1A (male > female) and PDE3B (male < female) were sex dependent; PDE2A, PDE4D, and PDE5A were sex independent. Barrier function, P(s), was determined from measures of albumin flux across confluent primary cultured microvessel XY and XX EC monolayers. Consistent with intact in situ microvessels, basal monolayer P(s) did not differ between XY (1.7 +/- 0.2 x 10(-6) cm/s; n = 8) and XX (1.8 +/- 0.1 x 10(-6) cm/s; n = 10) EC. Cilostazol, a PDE3 inhibitor, reduced (11%, P < 0.05) P(s) in XX, not XY, cells. These findings demonstrate the presence and maintenance of intrinsic sex-related differences in gene expression and cellular phenotype by microvascular EC in a gonadal-hormone-free environment. Furthermore, intrinsic cell-sex likely contributes significantly to sexual dimorphism in cardiovascular function.

Twentieth century surge of excess adult male mortality

“…Moreover, animal models further show greater intrinsic male cell vulnerability in experimental conditions. Vascular endothelial cells from male rats are less resistant to vascular barrier challenge (37,38), whereas male-derived cardiomyocytes are more vulnerable to ischemia (39). Thus, greater male vulnerability in arterial function could produce excess male mortality from heart disease as this condition became more prevalent with the reduction of infections during the demographic transition.…”

Cardiovascular disease in transsexual persons treated with cross-sex hormones: reversal of the traditional sex difference in cardiovascular disease pattern

“…In a sex steroid-free environment, there are intrinsic sex-related differences in gene expression and cellular phenotype by microvascular endothelial cells. These intrinsic cell-sex specifics likely contribute significantly to sexual dimorphism in cardiovascular function (65).…”

Prenatal Testosterone Induces Sex-Specific Dysfunction in Endothelium-Dependent Relaxation Pathways in Adult Male and Female Rats1

“…One could speculate that excess androgens in adult males and females may have differential effects on the endothelium, which may contribute to the differences in the endothelial pathways affected. Indeed, sexrelated differences with respect to both endothelial signaling molecule expression and endothelium-dependent vascular function have been documented [51][52][53][54]. The contribution of T, if any, to the differential and sex-specific vascular endothelial function in the prenatal T-exposed adults warrants future investigation.…”