Mechanisms Responsible for Serotonin Vascular Reactivity Sex Differences in the Internal Mammary Artery

Abstract

BackgroundThe increased adverse cardiac events in women undergoing coronary artery bypass grafting are multifactorial and may include clinical, psychosocial, and biological factors. Potential contributing biological factors could include vascular hyperreactivity of the internal mammary artery (IMA) to endogenous vasoconstrictors in women, resulting in a predilection to myocardial ischemia. This study evaluated sex differences in serotonin and thromboxane A2 dependent vasoconstriction in human isolated IMA, with the mechanistic role of (1) the endothelium, (2) nitric oxide (NO), (3) prostaglandins, and (4) receptor activity investigated for any observed sex difference.Methods and ResultsViable isolated human IMA segments were obtained from 116 patients (44 women [mean age, 66.8±12.2 years] and 72 men [mean age, 66.6±10.4 years]) undergoing coronary artery bypass grafting. Cumulative concentration‐response curves for serotonin and thromboxane A2 mimetic, U46619, were determined and revealed an increased sensitivity to serotonin but not U46619 in women. This sex difference to serotonin was further assessed by the following: (1) endothelial denudation, (2) endothelial NO synthase inhibition and NO quantification using electron paramagnetic resonance, (3) cyclooxygenase inhibition and prostaglandin metabolite quantification using mass spectrometry, and (4) quantification of receptor activity status. The female hyperreactivity to serotonin was (1) abolished by endothelial denudation; (2) unaffected by NO synthase inhibition, with no difference in electron paramagnetic resonance–assessed NO levels; (3) abolished by cyclooxygenase inhibition (quantification of prostaglandins in IMA revealed a trend towards reduced 6‐keto prostaglandin F1α in female IMA; P=0.08); and (4) unrelated to receptor activity.ConclusionsThese data indicate that female IMAs are hyperreactive to serotonin but not U46619, with the former attributable to an endothelium‐dependent cyclooxygenase pathway.

Sex differences in the structure and function of rat middle cerebral arteries

“…Estrogen enhances the production of NO and other vasodilators ( 31 , 56 ), which would be expected to reduce myogenic tone. On the other hand, female MCA has a greater response to NO, a lower response to ANG-II and ET-1, and no response to thromboxane A 2 agonists ( 1 , 43 ). Many other factors that contribute to the regulation of cerebral vascular function have been reported, such as peroxisome proliferator-activated receptor-γ ( 11 ), estrogen receptors ( 86 ), transient receptor potential channels, integrins, and actin cytoskeletal dynamics that involving activation of protein kinase C, mitogen-activated protein kinases, and RhoA-Rho kinase pathways, etc.…”

Deletion of murine slc29a4 modifies vascular responses to adenosine and 5‐hydroxytryptamine in a sexually dimorphic manner

“…Relatively few studies have examined sex differences in the response to 5‐HT, with many of the studies on the vascular effects of 5‐HT in mice being conducted using male animals only. It has been reported that endothelium‐intact human internal mammary artery segments from women exhibit increased sensitivity to the contractile actions of 5‐HT compared to those from men (Lamin et al, 2018). It was established that this difference was due to enhanced contribution of the endothelial cyclooxygenase pathway to the 5‐HT effects in males versus females.…”

Endothelial Progenitor Cells and Macrophage Subsets Recruitment in Postischemic Mouse Hind Limbs

“…At different time points following HLI, hind limb muscles were harvested, and sections were stained with hematoxylin and eosin. Prior studies have shown that skeletal muscle fibers undergoing repair following injury have centralized nuclei [31], hence we assessed the number of muscle fibers with centralized nuclei [32, 33]. Our results showed the percentage of muscle fibers with centrally located nuclei/total myofiber increased from day 3 to day 14 (day 0 = 0.02 ± 0.01, day 1 = 0.01 ± 0.001, day 3 = 0.13 ± 0.01, day 7 = 0.31 ± 0.05, and day 14 = 2.52 ± 0.14 Fig.…”