Sex-dependent differences in vasomotor responses of older male and female humans.

Abstract

Background and Aims: Sex differences have been observed in several cardiovascular diseases, in terms of mortality and morbidity. Female patients experience worse clinical outcomes than their male counterparts. Although multiple mechanisms may be involved, sex differences in vascular reactivity of large and small blood vessels have not been investigated. This thesis aims to assess sex-dependent difference in vasoconstrictor responses of human vessels isolated from a variety of vascular beds from older patients (mean age 68 years) with and without existing coronary artery disease. Specific aims include evaluation of :(1a) sex differences in vascular responses of internal mammary artery (IMA) and saphenous vein (SV) segments from male and female patients undergoing CABG and (1b) mechanisms underlying sex dependent vascular responses. (2) sex differences in microvascular reactivity of vessels isolated from mediastinal and peripheral subcutaneous areas in patients with CAD. (3a) sex difference in vascular reactivity of subcutaneous microvessels from patients with no known CAD, undergoing elective non-cardiac surgery. (3b) subcutaneous microvascular reactivity of males and females patients with CAD to those without known CAD. Methods: This thesis used wire myography technique to assess functional changes in vasoconstrictor responses of isolated large conduit and small blood vessels. Concentration-response curves were formed for various vasoconstrictors including phenylephrine, serotonin, endothelin-1 and the thromboxane mimetic, U46619. Western blot analysis was employed to measure the biochemical parameters, including receptor abundance endothelin-1. Summary of major findings: Female IMA segments display hypersensitive responses to serotonergic and α₁-adrenergic receptor stimulation, compared to males. Blocking eNOS and/or cyclooxygenase revealed that prostaglandins account for in the observed α₁-adrenergic mediated sex differences. Biochemical analysis revealed increased density of 5HT2A [2A in subscript] receptors in the female IMA. Similar sex differences were observed in the pericardial microvessels of the same patient cohort, with females showing increased sensitivity to serotonergic and α₁-adrenergic receptor stimulation. Interestingly, no sex differences were observed in the peripheral subcutaneous microvessels of patients with existing CAD. In patients without known CAD, female subcutaneous microvessels were hypersensitive to serotonergic and α₁-adrenergic receptor stimulation, compared to matched males. When compared to subcutaneous microvessels of male and female patients without known CAD, male and female CAD patients exhibited increased sensitivity to a1- adrenergic agonist. Male CAD patients were also hypersensitive to serotonin and the thromboxane A₂ mimetic, U46619, relative to those without known CAD. Conclusions: For the first time, in a population cohort with a mean age of 68 years, female vascular hyper-reactivity in both large graft arteries (IMA) and microvessels has been demonstrated. Female vascular hypersensitivity is consistently seen in response to serotonergic and α₁-adrenergic receptor agonist. In part, this may be due to sex-differences in prostanoid activity. The IMA hyper-reactivity in the group of older women may contribute to their poorer outcomes following CABG and microvascular differences amongst patients without documented cardiovascular disease may pre-dispose them to hypertension.