Jianjie Wang

Intrinsic sex-specific differences in microvascular endothelial cell phosphodiesterases.

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.

Differential Coronary Microvascular Exchange Responses to Adenosine: Roles of Receptor and Microvessel Subtypes

Objective: To assess the role of adenosine receptors in the regulation of coronary microvascular permeability to porcine serum albumin (PsPSA).

Cardiovascular sex differences influencing microvascular exchange

The vital role of the cardiovascular (CV) system is maintenance of body functions via the matching of exchange to tissue metabolic demand. Sex-specific differences in the regulatory mechanisms of CV function and the metabolic requirements of men and women, respectively, have been identified and appreciated. This review focuses on sex differences of parameters influencing exchange at the point of union between blood and tissue, the microvasculature. Microvascular architecture, blood pressure (hydrostatic and oncotic), and vascular permeability, therefore, are discussed in the specific context of sex in health and disorders. It is notable that when sex differences exist, they are generally subtle but significant. In the aggregate, though, they can give rise to profoundly different phenotypes. The postulated mechanisms responsible for sex differences are attributed to genomics, epigenetics, and sex hormones. Depending on specific circumstances, the effect of the combined factors can range from insignificant to lethal. Identifying and understanding key signalling mechanisms bridging genomics/sex hormones and microvascular exchange properties within the scope of this review holds significant promise for sex-specific prevention and treatment of vascular barrier dysfunction.

Sex differences influencing micro‐ and macrovascular endothelial phenotype in vitro

Endothelial dysfunction is an early hallmark of multiple disease states that also display sex differences with respect to age of onset, frequency and severity. Results of in vivo studies of basal and stimulated microvascular barrier function revealed sex differences that are difficult to ascribe to specific cells or environmental factors. The present study evaluated endothelial cells (EC) isolated from macro‐ and/or microvessels of reproductively mature rats under the controlled conditions of low‐passage culture aiming to test the assumption that EC phenotype would be sex independent. The primary finding was that EC, regardless of where they are derived, retain a sex‐bias in low‐passage culture, independent of varying levels of reproductive hormones. The implications of the present study include the fallacy of expecting a universal set of mechanisms derived from study of EC from one sex and/or one vascular origin to apply uniformly to all EC under unstimulated conditions, and no less in disease.