We found that the human syntenic regions corresponding to four of the six QTL regions detected in our post-menopausal cohort () were also shown to influence blood pressure in a genome-wide linkage study of systolic and diastolic blood pressure performed in a Quebec Family Study 
, although sex-specific analysis was not reported. The regions span BP-pm1
on rat chromosome 13, BP-pm2
on rat chromosome 11, BP-pm3
on rat chromosome 2 and BP-pm4
on rat chromosome 4 () suggesting that orthologous genes in these regions might underlie hypertension susceptibility in both post-menopausal Dahl rats and humans.
Given that loss or reduction in estrogen levels has been implicated as a key permissive factor in the increased incidence of hypertension and cardiovascular disease in post-menopausal women 
, it was unexpected that clinical estrogen/progestin replacement studies would not lead to the expected benefits, but in fact showed adverse cardiovascular events of hormone therapy in aging women 
. These polar clinical observations demonstrate the importance of systematic study in validated polygenic hypertension models of post-menopausal hypertension, such as in biological post-menopausal F2 (Dahl S×R)-intercross rats, in order to gain insight into the phenotype effects and genetic determinants of post-menopausal hypertension, while controlling for major confounders of hypertension, such as diet, genetic heterogeneity, environmental factors and developmental programming 
Consistent with increased salt-sensitive hypertension in post-menopausal women 
, comparative analysis of 6 m-old pre-menopausal, 6 m-old ovariectomized female and 16 m-old post-menopausal F2 (Dahl S×R)-intercross rats demonstrates that menopause increases salt-sensitive hypertension as a quantitative trait affecting systolic, diastolic and mean arterial pressures. Given the parallel studies using identical genetic F2-intercross design, the detection of multiple distinct BP QTLs among biological post-menopausal, pre-menopausal and surgical post-menopausal F2 (Dahl S×R)-intercross rats demonstrates that post-menopausal hypertension as modeled in the 16 m-old F2 (Dahl S×R) intercross rats involves genetic mechanisms not implicated in early-onset pre-menopausal and surgical post-menopausal salt-sensitive hypertension. We note that for some BP QTLs (BP-pm2
, ) the S allele lowers blood pressure in the post-menopausal cohort in contrast to increasing blood pressure in all BP QTLs detected in pre-menopausal females 
and most BP QTLs detected in males 
, except for BP-m2
which is found in both post-menopausal and male populations having the same directional effect on BP, i.e., S allele decreasing BP 
. These findings further indicate that differential genetic mechanisms underlie salt-sensitive hypertension in biological post-menopausal, pre-menopausal and surgical post-menopausal F2 genetic cohorts. Moreover, our results demonstrate an aging component to polygenic susceptibility to post-menopausal salt-sensitive hypertension since 6 months old ovariectomized females do not recapitulate the loci influencing blood pressure in 16 months old post-menopausal females.
Analysis of reported BP-QTLs in other Dahl S intercrosses using different normotensive strains revealed that BP-pm1 and BP-pm3 chromosomal regions overlapped with some BP-QTLs detected in other male and female intercrosses (). This suggests that genes underlying BP-m1 and BP-m3 might affect salt-sensitive hypertension susceptibility independently of sex, environment and age, although identification of corresponding gene variants will be necessary to verify this hypothesis.
Post-menopausal significant and highly significant BP QTLs detected in other Dahl S intercrosses.
Altogether, detection of distinct post-menopausal BP QTLs, the failure of hormone replacement therapy to reverse clinical post-menopausal hypertension 
, and worse target organ complications despite equivalent anti-hypertensive interventions 
, suggests a putative de-repression paradigm. The loss of ovarian hormones and the ensuing post-menopausal microenvironment de-represses hypertension susceptibility genetic mechanisms, which then result in mechanistic set-point changes not reversed by hormone replacement therapy, similar to the non-reversibility of menopause by hormone replacement therapy 
. On the other hand, the non-detection of several BP QTLs previously identified in a pre-menopausal F2 (Dahl S×R)-intercross cohort 
suggest that these loci are ovarian hormone-dependent. These observations raise the hypothesis that presence or absence of ovarian hormones is critical in determining the specific genetic loci contributing to salt-sensitive hypertension and its target organ complications.
In conclusion, our study demonstrates the involvement of distinct genetic loci, and hence differential genetic mechanisms underlying susceptibility in pre-menopausal, post-menopausal and surgical post-menopausal salt-sensitive hypertension. While observations provide insight into the failure of hormone replacement therapy for post-menopausal salt-sensitive hypertension and its inadvertent worsening of cardiac events, more importantly these data provide compelling evidence to mandate the elucidation of genetic mechanisms in post-menopausal salt-sensitive hypertension as the a priori basis for much-needed prevention and intervention strategies.