Endothelial Dysfunction as a Genetic Predictor for Bone Mass

Investigation of endothelial dysfunction as a genetic predictor of low bone mass and cognitive decline in postmenopausal females

Postmenopausal health has emerged as an important public health concern in India. During postmenopause, abrupt hormone and endocrine changes occur, which impact on the physiology and as a result, body becomes vulnerable to several health problems including osteoporosis, cardiovascular diseases, diabetes and cognitive impairment. Clinically, it is evident that first risky step in the series of adverse events that leads to these diseases is endothelial dysfunction (17353456). Endothelial dysfunction is a systemic pathological state of endothelium (inner lining of the blood vessels) which results because of imbalance between vasodilating and vasoconstricting substances produced by (or acting on) the endothelium. Generally, it is considered as reduction in endothelium dependent vasodilation resulting from diminished bioactivity of local vasodilatory factors especially nitric oxide (NO) (15643116). Since, it silently triggers the events much before the disease manifests, hence controlling it can prevent some adverse clinical outcomes. It aroused the interest of researchers because endothelial dysfunction is modifiable and may be reversible (9247501). Consequently, the predictive effect of endothelial dysfunction has been revealed in cardiovascular disease (11073878), diabetes (10882379), hypertension (11041120), stroke (11811384) and alzheimer’s disease (24224133). However, the predictive effect of endothelial dysfunction in two most likely events of postmenopause i.e. declining bone mass and cognition were investigated scarcely except few reports Worldwide (Sanada, Hiroyuki, 23740584) and no report from India.

Both low bone mass and impaired cognition are clinical hallmarks of Alzheimer’s disease (AD) (21187587,19661621), chronic kidney disease (20395370, 24583984), cardiovascular disease (15246921,24351701) and Stroke (11136913, 25104848) and are influenced by postmenopause state marked by declined estrogen. Literature has revealed that estrogen receptors are present on vascular endothelial beds that enhance bioavailability of NO, suggesting a direct influence of estrogen on endothelium and bone (Mendelsohn ME et al. 1999). Hormone replacement therapy (HRT) in postmenopausal females improves endothelial function and BMD proposing a link between endothelial dysfunction, estrogen and bone mass (Felson DT etal . 1993). Animal studies have also confirmed that blood flow in bone is associated with bone formation and mineralization (Kelly PJ et al. 1990) and inhibition of NO production (endothelial dysfunction) in rats resulted in marked bone loss (Kasten TP et al. 1994).

Steroid hormone receptors are present in the brain which regulates the transcription of many genes involved in cognition whereby hormonal imbalances disrupt receptor activation leading to cognitive attrition (Mani SK et al. 2009). Postmenopausal women with higher levels of endogenous estradiol showed better semantic memory than do those deficient in the estrogen and treatment of estradiol improves executive function in them (Ryan J et al. 2010, Marinho RM et al. 2008)

Not every postmenopausal female has endothelial dysfunction but it impacts much before in those females who are likely to suffer from such chronic health problems in years coming ahead. Since, endothelial function is maintained by the interaction of vasodilatory and vasocontricting molecules then, investigation of those genes that influence endothelial dysfunction for low bone mass and impaired cognition will be very informative for the early diagnosis, prevention of adverse outcomes and therapeutics. In this regard, three candidates i.e endothelial nitric oxide synthase (eNOS), angiotensin converting enzyme (ACE) and vascular endothelial growth factor (VEGF) genes which are responsible for inducing NO bioavailability (16162616) in the endothelium, generation of super oxide anions that degrade NO (10334805) and induction of angiogenesis (11795595 ) will be investigated for their role in endothelial dysfunction in postmenopausal females of Northwest India.

National Status

Right from the first report by Das (1435400) on the role of free radicals mediated endothelial dependent acute myocardial infarction, several studies have been carried out to investigate the association of endothelial dysfunction with hypertensive disorders in pregnancy (25538909), preeclampsia (24757293), diabetes and coronary artery disease (CAD) (12723648), CKD (24930933), psoriatic arthritis (24698261) and idiopathic nephrotic syndrome (24583419). However, no study investigated the role of endothelial dysfunction with bone mass and cognition in India so far.

eNOS, ACE and VEGF gene polymorphism:

eNOS, ACE and VEGF gene polymorphism in relation to several disorders have been checked in india, but investigation of these genes in relation to endothelial dysfunction has been seen in limited studies. eNOS gene polymorphism in relation to endothelial dysfunction has been checked for CAD (23182401, 23153979, 22045428), preeclampsia (22958187, 21424903,21376097, 20047583), diabetic nephropathy (18401556) and chronic obstructive pulmonary disease (COPD) (17658478).

ACE gene polymorphism in relation to endothelial dysfunction has been examined for Behcet disease (24188936) and essential hypertension (19379721). VEGF gene polymorphism in endothelial dysfunction has been investigated for chronic renal insufficiency (18413200)

International status:

In order to understand the genetic contribution of endothelial dysfunction, many studies have been carried out in relation to cardiovascular disease (11073878), diabetes (10882379), hypertension (11041120), stroke (11811384) and alzheimer’s disease (24224133) but the genetic contribution of endothelial dysfunction in relation to low bone mass and cognitive impairment has not been done so far. However, some reports have shown that endothelial dysfunction is associated with low bone mass (osteoporosis) (Sanada, Hiroyuki) and cognitive decline (23740584, 23814681)

Endothelial Nitric Oxide Synthase gene (eNOS or NOS3, ecNOS):

eNOS (OMIM: 163729) is a 21 kb gene localized on 7q36.1 and contains 26 exons. It synthesizes NO in endothelial cells from L-arginine which plays central role in vasodilation and is vital for healthy endothelium. Several polymorphic variations of the gene encoding eNOS are now known and have been investigated with respect to several diseases. Interestingly, some reports showed significant associations with diseases whereas others showed contradictory results. The reasons of these discrepancies are many including inadequate statistical power, different ethnicities, different methods of selecting cohort and involving interactions of the other genes. Several polymorphisms in noncoding and coding regions of the eNOS gene have been associated with several human diseases, including T-786C, A-922T, T-1486A, G894T, and a 27-bp repeat in intron 4. The most studied eNOS polymorphism is the single nucleotide polymorphism, G894T, in exon 7 that codes for an amino acid substitution (Glu298Asp).

eNOS 894T allele of G894T polymorphism was found to be associated with decreased eNOS activity and endothelial dysfunction (11668050). T allele of this polymorphism is significantly associated with diabetic nephropathy in type 2 diabetes mellitus (22313046). It is also associated with endothelial dysfunction and higher levels of von Willebrand factor in young myocardial patients (16337503). This allele along with 27bp tandem repeat in intron4 (4b/a) was found to be associated with Fabry’s disease (12121349). C allele of T786C polymorphism is observed to be genetic risk marker for endothelial dysfunction in type 2 diabetic patients (16401309) and insulin resistance (23031426). Glu298Asp polymorphism was found to be associated with endothelial dysfunction in coronary heart disease (20459417) and metabolic syndrome (21816783). T-786C and Glu298Asp polymorphism affects the fore arm blood flow response in pulmonary hypertension (12651037). Promoter (T786C) but not exon 7 (G894T) polymorphism is associated with training induced correction of endothelial dysfunction (12907461). Asp298 allele was observed to influence endothelial dysfunction in young Canadian men (15994775). “a” allele of intron 4a/b polymorphism is a risk factor for microvascular endothelial dysfunction in slow coronary flow (23811833) and sickle cell disease (25263931). Several studies demonstrated that polymorphisms within eNOS do not associate with microalbumineria in hypertensive men (19279989), chronic kidney disease (20849252) and in asthma (15115168).