Abstract
Background and purposeMale-female differences may significantly impact stroke prevention and treatment in men and women, however underlying mechanisms for sexual dimorphism in stroke are not understood. We previously found in males that cerebral ischemia upregulates contractile receptors in cerebral arteries, which is associated with lower blood flow. The present study investigates if cerebral arteries from men and women differ in cerebrovascular receptor upregulation.Experimental approachFreshly obtained human cerebral arteries were placed in organ culture, an established model for studying receptor upregulation. 5-hydroxtryptamine type 1B (5-HT1B), angiotensin II type 1 (AT1) and endothelin-1 type A and B (ETA and ETB) receptors were evaluated using wire myograph for contractile responses, real-time PCR for mRNA and immunohistochemistry for receptor expression.Key resultsVascular sensitivity to angiotensin II and endothelin-1 was markedly lower in cultured cerebral arteries from women as compared to men. ETB receptor-mediated contraction occurred in male but not female arteries. Interestingly, there were similar upregulation in mRNA and expression of 5-HT1B, AT1, and ETB receptors and in local expression of Ang II after organ culture.Conclusions and ImplicationsIn spite of receptor upregulation after organ culture in both sexes, cerebral arteries from women were significantly less responsive to vasoconstrictors angiotensin II and endothelin-1 as compared to arteries from men. This suggests receptor coupling and/or signal transduction mechanisms involved in cerebrovascular contractility may be suppressed in females. This is the first study to demonstrate sex differences in the vascular function of human brain arteries.
Highlights
Sexual dimorphism is observed in cerebral ischemia as demonstrated by a higher incidence of stroke in men than in women throughout much of the lifespan [1,2,3]
We report similar increase in receptor mRNA and receptor expression in all vessels after organ culture, but the contractile responses differ markedly between the sexes, with female arteries being less responsive to vasoconstrictors angiotensin II (Ang II) and ET-1
Contractile responses to 5-carboxamidotryptamine. 5HT1B receptor-mediated contraction was studied by cumulative application of increasing concentrations of the agonist 5-CT. 5-CT induced contractile responses that followed a monophasic concentration-response curve (Figure 1A)
Summary
Sexual dimorphism is observed in cerebral ischemia as demonstrated by a higher incidence of stroke in men than in women throughout much of the lifespan [1,2,3]. The underlying mechanisms for male-female differences in stroke are not established, many studies point to a role for estrogen. Male-female differences may significantly impact stroke prevention and treatment in men and women, underlying mechanisms for sexual dimorphism in stroke are not understood. We previously found in males that cerebral ischemia upregulates contractile receptors in cerebral arteries, which is associated with lower blood flow. The present study investigates if cerebral arteries from men and women differ in cerebrovascular receptor upregulation. Experimental approach: Freshly obtained human cerebral arteries were placed in organ culture, an established model for studying receptor upregulation. Experimental approach: Freshly obtained human cerebral arteries were placed in organ culture, an established model for studying receptor upregulation. 5-hydroxtryptamine type 1B (5-HT1B), angiotensin II type 1 (AT1) and endothelin-1 type A and B (ETA and ETB) receptors were evaluated using wire myograph for contractile responses, real-time PCR for mRNA and immunohistochemistry for receptor expression
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